TY  - JOUR
AB  - Cigarette smoking is the leading risk factor for COPD and lung cancer establishment. Epidemiologically, COPD patients are 6.35 times more likely to develop lung cancer. To mimic COPD, we exposed mice to nose-only cigarette smoke and used human samples of lung adenocarcinoma patients according to the smoking and COPD status. Smoking C57Bl/6N mice had higher enlargement of alveoli, deposition of collagen and mucus production, associated to the release of IL-1-like cytokines, such as IL-1α and IL-1β at early time points and IL-18 at later time points. AIM2 expression was higher in lung recruited dendritic cells and macrophages in smoking mice, associated to the activation of caspase-11, rather than caspase-1. In support,129Sv mice, which are dysfunctional for caspase-11, had lower collagen deposition and mucus production, associated to lower release of IL-1-like and fibrotic TGFβ. Interestingly, higher expression of AIM2 in non-cancerous tissue of smoking COPD adenocarcinoma patients was correlated to a higher hazard ratio of poor survival rate than in patients who presented lower levels of AIM2. We found that AIM2 inflammasome is at the crossroad between COPD and lung cancer in that its higher presence is correlated to lower survival rate of smoking COPD adenocarcinoma patients.
AU  - Colarusso, C.*
AU  - Terlizzi, M.*
AU  - Lamort, A.-S.
AU  - Cerqua, I.*
AU  - Roviezzo, F.*
AU  - Stathopoulos, G.T.
AU  - Pinto, A.*
AU  - Sorrentino, R.*
C1  - 62193
C2  - 50693
SP  - 1057-1071
TI  - Caspase-11 and AIM2 inflammasome are involved in smoking-induced COPD and lung adenocarcinoma.
JO  - Oncotarget
VL  - 12
IS  - 11
PY  - 2021
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Transcriptional cyclin-dependent kinases regulate all phases of transcription. Cyclin-dependent kinase 9 (CDK9) has been implicated in the regulation of promoter-proximal pausing of RNA polymerase II and more recently in transcription termination. Study of the substrates of CDK9 has mostly been limited to in vitro approaches that lack a quantitative assessment of CDK9 activity. Here we analyzed the cellular phosphoproteome upon inhibition of CDK9 by combining analog-sensitive kinase technology with quantitative phosphoproteomics in Raji B-cells. Our analysis revealed the activity of CDK9 on 1102 phosphosites quantitatively, and we identified 120 potential cellular substrates. Furthermore, a substantial number of CDK9 substrates were described as splicing factors, highlighting the role of CDK9 in transcription-coupled splicing events. Based on comparison to in vitro data, our findings suggest that cellular context fundamentally impacts the activity of CDK9 and specific selection of its substrates.
AU  - Decker, T.-M.
AU  - Forné, I.*
AU  - Straub, T.*
AU  - Elsaman, H.
AU  - Ma, G.
AU  - Shah, N.
AU  - Imhof, A.*
AU  - Eick, D.
C1  - 57695
C2  - 47856
SP  - 6934-6943
TI  - Analog-sensitive cell line identifies cellular substrates of CDK9.
JO  - Oncotarget
VL  - 10
IS  - 65
PY  - 2019
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in (OR=0.44, value=3.27x10 in overall lung cancer and OR=0.41, value=9.71x10 in non-small cell lung cancer), (OR=0.73, value=1.01x10 in adenocarcinoma) and (OR=1.82, value=7.62x10 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
AU  - Li, Y.*
AU  - Xiao, X.*
AU  - Bossé, Y.*
AU  - Gorlova, O.*
AU  - Gorlov, I.*
AU  - Han, Y.*
AU  - Byun, J.*
AU  - Leighl, N.*
AU  - Johansen, J.S.*
AU  - Barnett, M.*
AU  - Chen, C.*
AU  - Goodman, G.*
AU  - Cox, A.*
AU  - Taylor, F.*
AU  - Woll, P.*
AU  - Wichmann, H.-E.
AU  - Manz, J.
AU  - Muley, T.*
AU  - Risch, A.*
AU  - Rosenberger, A.*
AU  - Han, J.*
AU  - Siminovitch, K.*
AU  - Arnold, S.M.*
AU  - Haura, E.B.*
AU  - Bolca, C.*
AU  - Holcatova, I.*
AU  - Janout, V.*
AU  - Kontic, M.*
AU  - Lissowska, J.*
AU  - Mukeria, A.*
AU  - Ognjanovic, S.*
AU  - Orlowski, T.M.*
AU  - Scelo, G.*
AU  - Swiatkowska, B.*
AU  - Zaridze, D.*
AU  - Bakke, P.*
AU  - Skaug, V.*
AU  - Zienolddiny, S.*
AU  - Duell, E.J.*
AU  - Butler, L.M.*
AU  - Houlston, R.*
AU  - Artigas, M.S.*
AU  - Grankvist, K.*
AU  - Johansson, M.*
AU  - Shepherd, F.A.*
AU  - Marcus, M.W.*
AU  - Brunnström, H.*
AU  - Manjer, J.*
AU  - Melander, O.*
AU  - Müller, D.C.*
AU  - Overvad, K.*
AU  - Trichopoulou, A.*
AU  - Tumino, R.*
AU  - Liu, G.*
AU  - Bojesen, S.E.*
AU  - Wu, X.*
AU  - Le Marchand, L.*
AU  - Albanes, D.*
AU  - Bickeböller, H.*
AU  - Aldrich, M.C.*
AU  - Bush, W.S.*
AU  - Tardón, A.*
AU  - Rennert, G.*
AU  - Dawn Teare, M.*
AU  - Field, J.K.*
AU  - Kiemeney, L.A.*
AU  - Lazarus, P.*
AU  - Haugen, A.*
AU  - Lam, S.*
AU  - Schabath, M.B.*
AU  - Andrew, A.S.*
AU  - Bertazzi, P.A.*
AU  - Pesatori, A.C.*
AU  - Christiani, D.C.*
AU  - Caporaso, N.*
AU  - McKay, J.D.*
AU  - Brennan, P.*
AU  - Hung, R.J.*
AU  - Amos, C.I.*
C1  - 55687
C2  - 46467
SP  - 1760-1774
TI  - Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.
JO  - Oncotarget
VL  - 10
IS  - 19
PY  - 2019
SN  - 1949-2553
ER  - 

TY  - JOUR
AU  - Ingold, I.
AU  - Conrad, M.
C1  - 53594
C2  - 44920
SP  - 22241-22242
TI  - Selenium and iron, two elemental rivals in the ferroptotic death process.
JO  - Oncotarget
VL  - 9
IS  - 32
PY  - 2018
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Human carbonic anhydrase (CA) IX has emerged as a promising anticancer target and a diagnostic biomarker for solid hypoxic tumors. Novel fluorinated CA IX inhibitors exhibited up to 50 pM affinity towards the recombinant human CA IX, selectivity over other CAs, and direct binding to Zn(II) in the active site of CA IX inducing novel conformational changes as determined by X-ray crystallography. Mass spectrometric gas-analysis confirmed the CA IX-based mechanism of the inhibitors in a CRISPR/Cas9-mediated CA IX knockout in HeLa cells. Hypoxia-induced extracellular acidification was significantly reduced in HeLa, H460, MDA-MB-231, and A549 cells exposed to the compounds, with the IC50 values up to 1.29 nM. A decreased clonogenic survival was observed when hypoxic H460 3D spheroids were incubated with our lead compound. These novel compounds are therefore promising agents for CA IXspecific therapy.
AU  - Kazokaite, J.*
AU  - Niemans, R.*
AU  - Dudutiene, V.*
AU  - Becker, H.M.*
AU  - Leitans, J.*
AU  - Zubriene, A.*
AU  - Baranauskiene, L.*
AU  - Gondi, G.
AU  - Zeidler, R.
AU  - Matuliene, J.*
AU  - Tars, K.*
AU  - Yaromina, A.*
AU  - Lambin, P.*
AU  - Dubois, L.J.*
AU  - Matulis, D.*
C1  - 53837
C2  - 45067
SP  - 26800-26816
TI  - Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells.
JO  - Oncotarget
VL  - 9
IS  - 42
PY  - 2018
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Hepatitis B virus (HBV) infection is a prominent cause of hepatocellular carcinoma (HCC) but the underlying molecular mechanisms are complex and multiple pathways have been proposed such as the activation of the Wnt-/β-catenin-signalling and dysregulation of E-cadherin/β-catenin adherens junctions. This study aimed to identify mechanisms of how HBV infection and replication as well as HBV X protein (HBx) gene expression in the context of an HBV genome influence Wnt-/β-catenin-signalling and formation of adherens junctions and to which extent HBx contributes to this. Regulation of E-cadherin/β-catenin junctions and β-catenin-signalling as well as the role of HBx were investigated using constructs transiently or stably inducing replication of HBV+/-HBx in hepatoma cell lines. In addition, HCC and adjacent non-tumorous tissue samples from HBV-infected HCC patients and drug interference in HBV-infected cells were studied. Although HBV did not alter overall expression levels of E-cadherin or β-catenin, it diminished their cell surface localization resulting in nuclear translocation of β-catenin and activation of its target genes. In addition, HBV gene expression increased the amount of phosphorylated c-Src kinase. Treatment with Src kinase inhibitor Dasatinib reduced HBV replication, prevented adherens junction disassembly and reduced β-catenin-signalling, while Sorafenib only did so in cells with mutated β-catenin. Interestingly, none of the HBV induced alterations required HBx. Thus, HBV stimulated β-catenin-signalling and induced disassembly of adherens junctions independently of HBx through Src kinase activation. These pathways may contribute to hepatocellular carcinogenesis and seem to be more efficiently inhibited by Dasatinib than by Sorafenib.
AU  - von Olshausen, G.*
AU  - Quasdorff, M.*
AU  - Bester, R.
AU  - Arzberger, S.
AU  - Ko, C.
AU  - van de Klundert, M.
AU  - Zhang, K.
AU  - Odenthal, M.*
AU  - Ringelhan, M.
AU  - Niessen, C.M.*
AU  - Protzer, U.
C1  - 54436
C2  - 45574
SP  - 33947-33960
TI  - Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion.
JO  - Oncotarget
VL  - 9
IS  - 74
PY  - 2018
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - The potent transcription inhibitor Actinomycin D is used with several cancers. Here, we report the discovery that this naturally occurring antibiotic inhibits two human neutral aminopeptidases, the cell-surface alanine aminopeptidase and intracellular methionine aminopeptidase type 2. These metallo-containing exopeptidases participate in tumor cell expansion and motility and are targets for anticancer therapies. We show that the peptide portions of Actinomycin D and Actinomycin X are not required for effective inhibition, but the loss of these regions changes the mechanism of interaction. Two structurally less complex Actinomycin D analogs containing the phenoxazone chromophores, Questiomycin A and Actinocin, appear to be competitive inhibitors of both aminopeptidases, with potencies similar to the non-competitive macrocyclic parent compound ( in the micromolar range). The mode of action for all four compounds and both enzymes was demonstrated by molecular modeling and docking in the corresponding active sites. This knowledge gives new perspectives to Actinomycin D's action on tumors and suggests new avenues and molecules for medical applications.
AU  - Wȩglarz-Tomczak, E.*
AU  - Talma, M.*
AU  - Giurg, M.*
AU  - Westerhoff, H.V.*
AU  - Janowski, R.
AU  - Mucha, A.*
C1  - 53871
C2  - 45019
SP  - 29365-29378
TI  - Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs.
JO  - Oncotarget
VL  - 9
IS  - 50
PY  - 2018
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Epidemiological studies show a significant increase in ischemic heart disease (IHD) incidence associated with total external gamma-ray dose among Mayak plutonium enrichment plant workers. Our previous studies using mouse models suggest that persistent alteration of heart metabolism due to the inhibition of peroxisome proliferator-activated receptor (PPAR) alpha accompanies cardiac damage after high doses of ionising radiation. The aim of the present study was to elucidate the mechanism of radiation-induced IHD in humans. The cardiac proteome response to irradiation was analysed in Mayak workers who were exposed only to external doses of gamma rays. All participants were diagnosed during their lifetime with IHD that also was the cause of death. Label-free quantitative proteomics analysis was performed on tissue samples from the cardiac left ventricles of individuals stratified into four radiation dose groups (0 Gy, < 100 mGy, 100-500 mGy, and > 500 mGy). The groups could be separated using principal component analysis based on all proteomics features. Proteome profiling showed a dose-dependent increase in the number of downregulated mitochondrial and structural proteins. Both proteomics and immunoblotting showed decreased expression of several oxidative stress responsive proteins in the irradiated hearts. The phosphorylation of transcription factor PPAR alpha was increased in a dose-dependent manner, which is indicative of a reduction in transcriptional activity with increased radiation dose. These data suggest that chronic external radiation enhances the risk for IHD by inhibiting PPAR alpha and altering the expression of mitochondrial, structural, and antioxidant components of the heart.
AU  - Azimzadeh, O.
AU  - Azizova, T.V.*
AU  - Merl-Pham, J.
AU  - Subramanian, V.
AU  - Bakshi, M.V.
AU  - Moseeva, M.*
AU  - Zubkova, O.*
AU  - Hauck, S.M.
AU  - Anastasov, N.
AU  - Atkinson, M.J.
AU  - Tapio, S.
C1  - 49042
C2  - 41611
CY  - Orchard Park
SP  - 9067-9078
TI  - A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers.
JO  - Oncotarget
VL  - 8
IS  - 6
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - In gene therapy, effective and selective suicide gene expression is crucial. We exploited the endogenous Long INterspersed Element-1 (L1) machinery often reactivated in human cancers to integrate the Herpes Simplex Virus Thymidine Kinase (HSV-TK) suicide gene selectively into the genome of cancer cells. We developed a plasmid-based system directing HSV-TK expression only when reverse transcribed and integrated in the host genome via the endogenous L1 ORF1/2 proteins and an Alu element. Delivery of these new constructs into cells followed by Ganciclovir (GCV) treatment selectively induced mortality of L1 ORF1/2 protein expressing cancer cells, but had no effect on primary cells that do not express L1 ORF1/2. This novel strategy for selective targeting of tumour cells provides high tolerability as the HSV-TK gene cannot be expressed without reverse transcription and integration, and high selectivity as these processes take place only in cancer cells expressing high levels of functional L1 ORF1/2.
AU  - Chendeb, M.*
AU  - Schneider, R.
AU  - Davidson, I.*
AU  - Fadloun, A.
C1  - 50952
C2  - 42760
CY  - Orchard Park
SP  - 38239-38250
TI  - Selective elimination of long INterspersed element-1 expressing tumour cells by targeted expression of the HSV-TK suicide gene.
JO  - Oncotarget
VL  - 8
IS  - 24
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory. We show here that T cells redirected to tumor cells by trAbs strongly upregulate CTLA-4 expression in vitro and in vivo. This suggested that blocking of CTLA-4 in combination with trAb treatment enhances T-cell activation in a tumor-selective manner. However, when mice were challenged with melanoma cells and subsequently treated with antibodies, there was only a moderate beneficial effect of the combinatorial approach in vivo with regard to direct tumor destruction in comparison to trAb therapy alone. By contrast, a significantly improved vaccination effect was obtained by CTLA-4 blocking during trAb-dependent immunization. This resulted in enhanced rejection of melanoma cells given after pre-immunization. The improved immunologic memory induced by the combinatorial approach correlated with an increased humoral antitumor response as measured in the sera and an expansion of CD4+ memory T cells found in the spleens.
AU  - Deppisch, N.
AU  - Ruf, P.*
AU  - Eißler, N.
AU  - Lindhofer, H.*
AU  - Mocikat, R.
C1  - 50315
C2  - 42092
SP  - 4520-4529
TI  - Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition.
JO  - Oncotarget
VL  - 8
IS  - 3
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Hematopoietic Stem Cells (HSCs) generate blood and immune cells through a hierarchical process of differentiation. Genes that regulate this process are of great interest for understanding normal and also malignant hematopoiesis. Surprisingly, however, very little is known about long-non-coding RNAs (lncRNA) in HSCs. Neat1 is a lncRNA that plays a major role in the formation of sub-nuclear structures called paraspeckles, and was reported to regulate proliferation and differentiation in other cells types. We detected Neat1 expression using RNA-seq data and RT-qPCR in HSCs, progenitors and effector immune cells, by specific detection of its isoforms. Neat1 is highly expressed in stem and progenitor cells, yet it shows significant reduction in granulocytes. Microscopically, Neat1 is detected as sharp nuclear foci. Paraspeckle proteins NONO and PSPC1 are detected as aggregated nuclear foci in fresh primary hematopoietic cells, and in cultured cells. Induction of differentiation in vitro was found to enhance Neat1 expression. Taken together, our data demonstrate for the first time the expression of Neat1 and paraspeckles formation in HSCs and along hematopoiesis.
AU  - Fallik, N.*
AU  - Bar-Lavan, Y.*
AU  - Greenshpan, Y.*
AU  - Goldstein, O.*
AU  - Grosch, M.
AU  - Drukker, M.
AU  - Gazit, R.*
C1  - 52559
C2  - 44073
CY  - Orchard Park
SP  - 109575-109586
TI  - Neat1 in hematopoietic stem cells.
JO  - Oncotarget
VL  - 8
IS  - 65
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.g. topotecan (TOPO)). Despite aggressive treatment, NB may become resistant to chemotherapy. We investigated whether CDDP and TOPO treatment of NB cells interacts with the expression and function of proteins involved in regulating calcium signaling. Human neuroblastoma cell lines SH-SY5Y, IMR-32 and NLF were used to investigate the effects of CDDP and TOPO on cell viability, apoptosis, calcium homeostasis, and expression of selected proteins regulating intracellular calcium concentration ([Ca2+]i). In addition, the impact of pharmacological inhibition of [Ca2+]i-regulating proteins on neuroblastoma cell survival was studied. Treatment of neuroblastoma cells with increasing concentrations of CDDP (0.1-10 μM) or TOPO (0.1 nM-1 μM) induced cytotoxicity and increased apoptosis in a concentration- and time-dependent manner. Both drugs increased [Ca2+]i over time. Treatment with CDDP or TOPO also modified mRNA expression of selected genes encoding [Ca2+]i-regulating proteins. Differentially regulated genes included S100A6, ITPR1, ITPR3, RYR1 and RYR3. With FACS and confocal laser scanning microscopy experiments we validated their differential expression at the protein level. Importantly, treatment of neuroblastoma cells with pharmacological modulators of [Ca2+]i-regulating proteins in combination with CDDP or TOPO increased cytotoxicity. Thus, our results confirm an important role of calcium signaling in the response of neuroblastoma cells to chemotherapy and suggest [Ca2+]i modulation as a promising strategy for adjunctive treatment.
AU  - Florea, A.M.*
AU  - Varghese, E.*
AU  - McCallum, J.E.*
AU  - Mahgoub, S.*
AU  - Helmy, I.*
AU  - Varghese, S.*
AU  - Gopinath, N.*
AU  - Sass, S.
AU  - Theis, F.J.
AU  - Reifenberger, G.*
AU  - Büsselberg, D.*
C1  - 50643
C2  - 42657
CY  - Orchard Park
SP  - 22876-22893
TI  - Calcium-regulatory proteins as modulators of chemotherapy in human neuroblastoma.
JO  - Oncotarget
VL  - 8
IS  - 14
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Effectively targeting leukemia-initiating cells (LIC) in FLT3-ITD-mutated acute myeloid leukemia (AML) is crucial for cure. Tyrosine kinase inhibitors (TKI) have limited impact as single agents, failing to eradicate LIC in the bone marrow. Using primary AML samples and a patient-derived xenograft model, we investigated whether combining the FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) eliminates FLT3-ITD LIC and whether efficacy of this combination depends on co-existing mutations. Using multiparameter flow cytometry, we show FLT3-ITD occurs within the most primitive Lin(-)/CD33((+))/CD45(dim)/CD34(+) CD38(-) LIC compartment. Crenolanib alone could not target FLT3-ITD LIC in contact with niche cells while addition of AZA overcame stromal protection resulting in dramatically reduced clonogenic capacity of LIC in vitro and severely impaired engraftment in NSG mice. Strikingly, FLT3-mutated samples harboring TET2 mutations were completely resistant to crenolanib whereas neither NPM1 nor DNMT3A mutations influenced response. Conversely, primary AML LIC harboring either TET2, DNMT3A or NPM1 mutations did not show increased sensitivity to AZA. In summary, resistance of FLT3-ITD LIC to TKI depends on co-existing epigenetic mutations. However, AZA + crenolanib effectively abrogates stromal protection and inhibits survival of FLT3-ITD LIC irrespective of mutations, providing evidence for this combination as a means to suppress residual LIC.
AU  - Garz, A.K.*
AU  - Wolf, S.*
AU  - Grath, S.*
AU  - Gaidzik, V.I.*
AU  - Habringer, S.*
AU  - Vick, B.
AU  - Rudelius, M.*
AU  - Ziegenhain, C.*
AU  - Herold, S.*
AU  - Weickert, M.T.*
AU  - Smets, M.*
AU  - Peschel, C.*
AU  - Oostendorp, R.A.J.*
AU  - Bultmann, S.*
AU  - Jeremias, I.
AU  - Thiede, C.*
AU  - Döhner, K.*
AU  - Keller, U.*
AU  - Götze, K.S.*
C1  - 52558
C2  - 44072
CY  - Orchard Park
SP  - 108738-108759
TI  - Azacitidine combined with the selective FLT3 kinase inhibitor crenolanib disrupts stromal protection and inhibits expansion of residual leukemia-initiating cells in FLT3-ITD AML with concurrent epigenetic mutations.
JO  - Oncotarget
VL  - 8
IS  - 65
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Laryngeal cancer is a frequent malignancy originating from the squamous vocal epithelium in a multi-stage fashion in response to environmental carcinogens. Although most cases can be cured by surgery and/or radiotherapy, advanced and relapsing disease is common, and biomarkers of such dismal cases are urgently needed. The cancer genome of laryngeal cancers was recently shown to feature a signature of aberrant nuclear factor (NF)-kappa B activation, but this finding has not been clinically exploited. We analyzed primary tumor samples of 96 well-documented and longitudinally followed patients covering the whole spectrum of laryngeal neoplasia, including 21 patients with benign laryngeal diseases, 15 patients with dysplasia, 43 patients with early-stage carcinoma, and 17 patients with locally advanced carcinoma, for immunoreactivity of RelA, RelB, P50, and P52/P100, the main NF-kappa B subunits that activate transcription. Results were cross-examined with indices of tumor progression and survival. Interestingly, RelB expression increased with tumor stage, grade, and local extent. Moreover, patients displaying high RelB immunoreactivity exhibited statistically significantly poorer survival compared with patients featuring low levels of RelB expression (P = 0.018 by log-rank test). Using Cox regression analyses and tumor stage, local extent, grade and RelA/RelB immunoreactivity, we develop a new score that can independently predict survival of patients with laryngeal cancer. Hence we provide a simple and affordable NF-kappa B-based test to predict prognosis in laryngeal cancer.
AU  - Giopanou, I.*
AU  - Lilis, I.*
AU  - Papadaki, H.*
AU  - Papadas, T.*
AU  - Stathopoulos, G.T.
C1  - 52957
C2  - 44257
CY  - Orchard Park
SP  - 114019-114030
TI  - A link between ReIB expression and tumor progression in laryngeal cancer.
JO  - Oncotarget
VL  - 8
IS  - 69
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43x10(-9), DOCK3, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (alpha=8.9x10(-4)), the most significant associations were observed for SNPs rs10505477 (P=6.08x10(-4)) and rs6983267 (P=7.35x10(-4)) of CASC8, rs3802842 (P=8.98x10(-5), COLCA1,2), and rs12953717 (P=4.64x10(-4), SMAD7). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer.
AU  - Hofer, P.*
AU  - Hagmann, M.*
AU  - Brezina, S.*
AU  - Dolejsi, E.*
AU  - Mach, K.*
AU  - Leeb, G.*
AU  - Baierl, A.*
AU  - Buch, S.*
AU  - Sutterlüty-Fall, H.*
AU  - Karner-Hanusch, J.*
AU  - Bergmann, M.M.*
AU  - Bachleitner-Hofmann, T.*
AU  - Stift, A.*
AU  - Gerger, A.*
AU  - Rötzer, K.*
AU  - Karner, J.*
AU  - Stättner, S.*
AU  - Waldenberger, M.
AU  - Meitinger, T.
AU  - Strauch, K.
AU  - Linseisen, J.
AU  - Gieger, C.
AU  - Frommlet, F.*
AU  - Gsur, A.*
C1  - 52474
C2  - 44007
CY  - Orchard Park
SP  - 98623-98634
TI  - Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.
JO  - Oncotarget
VL  - 8
IS  - 58
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Aberrant B-cell receptor (BCR) signaling is known to contribute to malignant transformation. Two small molecule inhibitors targeting BCR pathway signaling include ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and idelalisib, a specific Phosphatidylinositol-4,5-bisphosphate 3-kinase delta (PI3Kd) inhibitor, both of which have been approved for use in haematological malignancies. Despite the identification of various diffuse large B-cell lymphoma (DLBCL) subtypes, mutation status alone is not sufficient to predict patient response and therapeutic resistance can arise. Herein we apply early molecular imaging across alternative activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL subtypes to investigate the effects of BCR pathway inhibition. Treatment with both inhibitors adversely affected cell growth and viability. These effects were partially predictable based upon mutation status. Accordingly, very early 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ( 18 F-FDG-PET) and 3'-deoxy-3'[18F]-fluorothymidine positron emission tomography ( 18 F-FLT-PET) reported tumour regression and reductions in tumour metabolism and proliferation upon treatment. Furthermore, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) identified alterations in the proteome of a model of ABC DLBCL upon treatment with ibrutinib or idelalisib. In conclusion we demonstrate that very early molecular imaging adds predictive value in addition to mutational status of DLBCL that may be useful in directing patient therapy.
AU  - Jacobs, L.*
AU  - Habringer, S.*
AU  - Slawska, J.*
AU  - Huber, K.
AU  - Hauf, E.*
AU  - Li, Z.*
AU  - Refaeli, Y.*
AU  - Schwaiger, M.*
AU  - Rudelius, M.*
AU  - Walch, A.K.
AU  - Keller, U.*
C1  - 52106
C2  - 43744
CY  - Orchard Park
SP  - 78917-78929
TI  - Functional imaging in combination with mutation status aids prediction of response to inhibiting B-cell receptor signaling in lymphoma.
JO  - Oncotarget
VL  - 8
IS  - 45
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - The development and progression of cancer can be ascribed to imbalances in gene regulation leading to aberrant cellular behavior. The loss of micro RNAs (miRNAs) exhibiting tumor-suppressive function has been demonstrated to be often causative for uncontrolled cell proliferation, migration or tissue infiltration. The installation of de novo tumor suppressive function by using pro-apoptotic miRNAs might be a promising therapeutic approach. In addition, there is a great demand for novel biomarkers for the prognosis of cancer, which prompted us to transfer a high content miRNA screening initially performed to identify bioprocess relevant miRNAs in Chinese hamster ovary (CHO) cells to human cancer cell lines . Analysis of screened miRNAs exhibiting strongest pro-apoptotic effects discovered globally and cross-species active candidates. The recovery rate of apoptosis inducing miRNAs was highest in the human ovarian carcinoma cell line SKOV3. Focusing on ovarian cell lines miR-1912, miR-147b and miR-3073a showed significant apoptosis induction in cell lines with different genetic background (SKOV3p53null, OVCAR3p53R248Q, TOV21G, TOV112Dp53R175H, A2780, A2780-cisp53K351N) alone and additive effects in combination with carboplatin. While expression analysis revealed a low endogenous expression of miR-1912 and miR-147b in SKOV3, miRNA expression was highly upregulated upon apoptosis induction using chemotherapeutics. Ectopic introduction of these miRNAs lead to enhanced activation of caspase-dependent death signaling and an induction of the pro-apoptotic proteins Bak1 and Bax and a reduced expression of Bcl2 and Bcl-xL. Finally, analysis of The Cancer Genome Atlas data revealed the expression of hsa-miR-147b-5p to show a positive influence on the median survival of ovarian cancer patients.
AU  - Kleemann, M.*
AU  - Bereuther, J.*
AU  - Fischer, S.*
AU  - Marquart, K.*
AU  - Hänle, S.*
AU  - Unger, K.
AU  - Jendrossek, V.*
AU  - Riedel, C.U.*
AU  - Handrick, R.*
AU  - Otte, K.*
C1  - 50842
C2  - 42661
SP  - 18773-18791
TI  - Investigation on tissue specific effects of pro-apoptotic micro RNAs revealed miR-147b as a potential biomarker in ovarian cancer prognosis.
JO  - Oncotarget
VL  - 8
IS  - 12
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Antibody-based immunotherapy represents a promising strategy to eliminate chemorefractory leukemic cells in acute myeloid leukemia (AML). In this study, we evaluated a novel Fc-engineered antibody against CD157 (MEN1112) for its suitability as immunotherapy in AML. CD157 was expressed in 97% of primary AML patient samples. A significant, albeit lower expression level of CD157 was observed within the compartment of leukemia-initiating cells, which are supposed to be the major source of relapse. In healthy donor bone marrow, CD157 was expressed on CD34+ cells. In ex vivo assays, MEN1112 triggered natural killer (NK) cell-mediated cytotoxicity against AML cell lines and primary AML cells. Compared to its parental analogue, the Fc-engineered antibody exhibited higher antibody dependent cellular cytotoxicity responses. Using NK cells from AML patients, we observed heterogeneous MEN1112-mediated cytotoxicity against AML cells, most likely due to well-documented defects in AML-NK cells and corresponding inter-patient variations in NK cell function. Cytotoxicity could not be correlated to the time after completion of chemotherapy. In summary, we could demonstrate that CD157 is strongly expressed in AML. MEN1112 is a promising antibody construct that showed high cytotoxicity against AML cells and warrants further clinical testing. Due to variability in NK-cell function of AML patients, the time of application during the course of the disease as well as combinatorial strategies might influence treatment results.
AU  - Krupka, C.
AU  - Lichtenegger, F.S.
AU  - Köhnke, T.
AU  - Bögeholz, J.*
AU  - Bücklein, V.L.
AU  - Roiss, M.
AU  - Altmann, T.
AU  - Do, T.U.*
AU  - Dusek, R.*
AU  - Wilson, K.D.*
AU  - Bisht, A.*
AU  - Terrett, J.*
AU  - Aud, D.*
AU  - Pombo-Villar, E.*
AU  - Rohlff, C.*
AU  - Hiddemann, W.*
AU  - Subklewe, M.
C1  - 51262
C2  - 42813
SP  - 35707-35717
TI  - Targeting CD157 in AML using a novel, Fc-engineered antibody construct.
JO  - Oncotarget
VL  - 8
IS  - 22
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Glycosylation in cancer is a highly dynamic process that has a significant impact on tumor biology. Further, the attachment of aberrant glycan forms is already considered a hallmark of the disease state. Mass spectrometry has become a prominent approach to analyzing glycoconjugates. Specifically, matrix-assisted laser desorption/ionisation -mass spectrometric imaging (MALDI-MSI) is a powerful technique that combines mass spectrometry with histology and enables the spatially resolved and label-free detection of glycans. The most common approach to the analysis of glycans is the use of mass spectrometry adjunct to PNGase F digestion and other chemical reactions. In the current study, we perform the analysis of formalin-fixed, paraffin-embedded (FFPE) tissues for natively occurring bioactive glycan fragments without prior digestion or chemical reactions using MALDI-FT-ICR-MSI. We examined 106 primary resected gastric cancer patient tissues in a tissue microarray and correlated native-occurring fragments with clinical endpoints, therapeutic targets such as epidermal growth factor receptor (EGFR) and HER2/neu expressions and the proliferation marker MIB1. The detection of a glycosaminoglycan fragment in tumor stroma regions was determined to be an independent prognostic factor for gastric cancer patients. Native glycan fragments were significantly linked to the expression of EGFR, HER2/neu and MIB1. In conclusion, we are the first to report the in situ detection of native-occurring bioactive glycan fragments in FFPE tissues that influence patient outcomes. These findings highlight the significance of glycan fragments in gastric cancer tumor biology and patient outcome.
AU  - Kunzke, T.
AU  - Balluff, B.*
AU  - Feuchtinger, A.
AU  - Buck, A.
AU  - Langer, R.*
AU  - Luber, B.*
AU  - Lordick, F.*
AU  - Zitzelsberger, H.
AU  - Aichler, M.
AU  - Walch, A.K.
C1  - 51627
C2  - 43323
SP  - 68012-68025
TI  - Native glycan fragments detected by MALDI-FT-ICR mass spectrometry imaging impact gastric cancer biology and patient outcome.
JO  - Oncotarget
VL  - 8
IS  - 40
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Generated by Quaking (QKI), circular RNAs (circRNAs) are newly recognised non-coding RNA (ncRNA) members characterised by tissue specificity, increased stability and enrichment within exosomes. Studies have shown that ionizing radiation (IR) can influence ncRNA transcription. However, it is unknown whether circRNAs or indeed QKI are regulated by IR. Microarray circRNA profiling and next generation sequencing revealed that circRNA expression was altered by low and medium dose exposure sourced predominantly from genes influencing the p53 pathway. CircRNAs KIRKOS-71 and KIRKOS-73 transcribed from the WWOX (WW Domain Containing Oxidoreductase) tumor suppressor (a p53 regulator) responded within hours to IR. KIRKOS-71 and KIRKOS-73 were present in exosomes yet exhibited differential transcript clearance between irradiated cell lines. Dual-quasar labelled probes and in-situ hybridization demonstrated the intercellular distribution of KIRKOS-71 and KIRKOS-73 predominantly within the perinucleus. QKI knockdown removed nuclear expression of these circRNAs with no significant effect on cytosolic KIRKOS-71 and KIRKOS-73. Distinct QKI transcription between cell lines and its augmented interaction with KIRKOS-71 and KIRKOS-73 was noted post IR. This foremost study provides evidence that QKI and circRNAs partake in the cellular irradiation response. KIRKOS-71 and KIRKOS-73 as stable secreted circRNAs may afford vital characteristics worth syphoning as promising diagnostic radiotherapy biomarkers.
AU  - O'Leary, V.B.
AU  - Smida, J.
AU  - Matjanovski, M.
AU  - Brockhaus, C.
AU  - Winkler, K.
AU  - Mörtl, S.
AU  - Ovsepian, S.V.
AU  - Atkinson, M.J.
C1  - 51565
C2  - 43313
CY  - Orchard Park
SP  - 78397-78409
TI  - The circRNA interactome-innovative hallmarks of the intra- and extracellular radiation response.
JO  - Oncotarget
VL  - 8
IS  - 45
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Breakage of the fragile site FRA16D disrupts the WWOX (WW Domain Containing Oxidoreductase) tumor suppressor gene in osteosarcoma. However, the frequency of breakage is not sufficient to explain the rate of WWOX loss in pathogenesis. The involvement of non-coding RNA transcripts is proposed due to their accumulation at fragile sites, where they are advocated to influence specific chromosomal regions associated with malignancy. The long ncRNA PARTICLE (promoter of MAT2A antisense radiation-induced circulating long non-coding RNA) is transiently elevated in response to irradiation and influences epigenetic silencing modification within WWOX. It now emerges that elevated PARTICLE levels are significantly associated with FRA16D non-breakage in OS patients. Although not associated with overall survival, high PARTICLE levels were found to be significantly linked to metastasis free outcome. The transcription of both PARTICLE and WWOX are transiently responsive to exposure to low doses of radiation in osteosarcoma cell lines. Herein, a relationship between WWOX and PARTICLE transcription is suggested in human osteosarcoma cell lines representing alternative genetic backgrounds. PARTICLE over-expression ameliorated WWOX promoter activity in U2OS harboring FRA16D non-breakage. It can be concluded that the lncRNA PARTICLE influences the WWOX tumor suppressor and in the absence of WWOX FRA16D breakage, it is associated with OS metastasis-free survival.
AU  - O'Leary, V.B.
AU  - Maugg, D.
AU  - Smida, J.
AU  - Baumhoer, D.*
AU  - Nathrath, M.*
AU  - Ovsepian, S.V.
AU  - Atkinson, M.J.
C1  - 51948
C2  - 43535
CY  - Orchard Park
SP  - 87431-87441
TI  - The long non-coding RNA PARTICLE is associated with WWOX and the absence of FRA16D breakage in Osteosarcoma patients.
JO  - Oncotarget
VL  - 8
IS  - 50
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - CD47, expressed on a variety of tumor cells, confers immune resistance by delivering an inhibitory "don't eat me" signal to phagocytic cells via its myeloid-specific receptor SIRPα. Recent studies have shown that blocking the CD47-SIRPα axis with CD47-directed antibodies or antibody-derivatives enhances phagocytosis and increases antitumor immune effects. However, CD47 expression on healthy cells creates an antigen sink and potential sites of toxicity, limiting the efficacy of CD47-directed therapies. In this study, we first characterized CD47 expression in Acute Myeloid Leukemia (AML) patients (n = 213) and found that CD47 is highly expressed on both AML bulk and stem cells irrespective of the disease state. Furthermore, to inhibit the CD47-SIRPα signaling pathway at the tumor site, we developed a so-called local inhibitory checkpoint monoclonal antibody (licMAB) by grafting the endogenous SIRPα domain to the N-terminus of the light chain of an antibody targeting CD33, a surface antigen expressed in AML. LicMABs selectively bind CD33-expressing cells even in the presence of a large CD33-negative CD47-positive antigen sink, stimulate phagocytosis of AML cells and eliminate AML cell lines and primary, patient-derived AML cells. Our findings qualify licMABs as a promising therapeutic approach to confine the benefit of disrupting the CD47-SIRPα axis to tumor antigen-expressing cells.
AU  - Ponce, L.P.*
AU  - Fenn, N.C.*
AU  - Moritz, N.*
AU  - Krupka, C.
AU  - Kozik, J.H.*
AU  - Lauber, K.*
AU  - Subklewe, M.
AU  - Hopfner, K.P.*
C1  - 50553
C2  - 42630
CY  - Orchard Park
SP  - 11284-11301
TI  - SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells.
JO  - Oncotarget
VL  - 8
IS  - 7
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - The Epstein-Barr virus (EBV) is etiologically associated with the development of multiple types of tumors, but it is unclear whether this diversity is due to infection with different EBV strains. We report a comparative characterization of SNU719, GP202, and YCCEL1, three EBV strains that were isolated from gastric carcinomas, M81, a virus isolated in a nasopharyngeal carcinoma and several well-characterized laboratory type A strains. We found that B95-8, Akata and GP202 induced cell growth more efficiently than YCCEL1, SNU719 and M81 and this correlated positively with the expression levels of the viral BHRF1 miRNAs. In infected B cells, all strains except Akata and B95-8 induced lytic replication, a risk factor for carcinoma development, although less efficiently than M81. The panel of viruses induced tumors in immunocompromised mice with variable speed and efficacy that did not strictly mirror their in vitro characteristics, suggesting that additional parameters play an important role. We found that YCCEL1 and M81 infected primary epithelial cells, gastric carcinoma cells and gastric spheroids more efficiently than Akata or B95-8. Reciprocally, Akata and B95-8 had a stronger tropism for B cells than YCCEL1 or M81. These data suggest that different EBV strains will induce the development of lymphoid tumors with variable efficacy in immunocompromised patients and that there is a parallel between the cell tropism of the viral strains and the lineage of the tumors they induce. Thus, EBV strains can be endowed with properties that will influence their transforming abilities and the type of tumor they induce.
AU  - Tsai, M.H.*
AU  - Lin, X.*
AU  - Shumilov, A.*
AU  - Bernhardt, K.*
AU  - Feederle, R.
AU  - Poirey, R.*
AU  - Kopp-Schneider, A.*
AU  - Pereira, B.*
AU  - Almeida, R.*
AU  - Delecluse, H.J.*
C1  - 50529
C2  - 42318
CY  - Orchard Park
SP  - 10238-10254
TI  - The biological properties of different Epstein-Barr virus strains explain their association with various types of cancers.
JO  - Oncotarget
VL  - 8
IS  - 6
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90a and Hsp90β, and the mitochondrial isoform Trap1. Hsp90a/β support a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90a/β and Trap1 are required for tumorigenesis. However, a direct and comparative genetic test in a mouse cancer model has not been done. Here we report the effects of deleting the Hsp90a or Trap1 genes in a mouse model of breast cancer. Neither Hsp90a nor Trap1 are absolutely required for mammary tumor initiation, growth and metastasis induced by the polyoma middle T-antigen as oncogene. However, they do modulate growth and lung metastasis in vivo and cell proliferation, migration and invasion of isolated primary carcinoma cells in vitro. Without Hsp90a, tumor burden and metastasis are reduced, correlating with impaired proliferation, migration and invasion of cells in culture. Without Trap1, the appearance of tumors is initially delayed, and isolated cells are affected similarly to those without Hsp90a. Analysis of expression data of human breast cancers supports the conclusion that this is a valid mouse model highlighting the importance of these molecular chaperones.
AU  - Vartholomaiou, E.*
AU  - Madon-Simon, M.*
AU  - Hagmann, S.*
AU  - Mühlebach, G.*
AU  - Wurst, W.
AU  - Floss, T.
AU  - Picard, D.*
C1  - 50778
C2  - 42640
CY  - Orchard Park
SP  - 17428-17442
TI  - Cytosolic Hsp90a and its mitochondrial isoform Trap1 are differentially required in a breast cancer model.
JO  - Oncotarget
VL  - 8
IS  - 11
PB  - Impact Journals Llc
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Enumeration of circulating tumor cells (CTCs) in peripheral blood with the gold standard CellSearchTM has proven prognostic value for tumor recurrence and progression of metastatic disease. Therefore, the further molecular characterization of isolated CTCs might have clinical relevance as liquid biopsy for therapeutic decision-making and to monitor disease progression. The direct analysis of systemic cancer appears particularly important in view of the known disparity in expression of therapeutic targets as well as epithelial-to-mesenchymal transition (EMT)-based heterogeneity between primary and systemic tumor cells, which all substantially complicate monitoring and therapeutic targeting at present. Since CTCs are the potential precursor cells of metastasis, their in-depth molecular profiling should also provide a useful resource for target discovery. The present review will discuss the use of systemically spread cancer cells as liquid biopsy and focus on potential target antigens.
AU  - Wang, H.*
AU  - Stoecklein, N.H.*
AU  - Lin, P.P.*
AU  - Gires, O.
C1  - 50495
C2  - 33286
SP  - 1884-1912
TI  - Circulating and disseminated tumor cells: Diagnostic tools and therapeutic targets in motion.
JO  - Oncotarget
VL  - 8
IS  - 1
PY  - 2017
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - A combined transcriptome and proteome analysis of mouse radiation-induced AMLs using two primary AMLs, cell lines from these primaries, another cell line and its in vivo passage is reported. Compared to haematopoietic progenitor and stem cells (HPSC), over 5000 transcriptome alterations were identified, 2600 present in all materials. 55 and 3 alterations were detected in the proteomes of the cell lines and primary/in vivo passage material respectively, with one common to all materials. In cell lines, approximately 50% of the transcriptome changes are related to adaptation to cell culture, and in the proteome this proportion was higher. An AML 'signature' of 17 genes/proteins commonly deregulated in primary AMLs and cell lines compared to HPSCs was identified and validated using human AML transcriptome data. This also distinguishes primary AMLs from cell lines and includes proteins such as Coronin 1, pontin/RUVBL1 and Myeloperoxidase commonly implicated in human AML. C-Myc was identified as having a key role in radiation leukaemogenesis. These data identify novel candidates relevant to mouse radiation AML pathogenesis, and confirm that pathways of leukaemogenesis in the mouse and human share substantial commonality.
AU  - Badie, C.*
AU  - Blachowicz, A.*
AU  - Barjaktarovic, Z.
AU  - Finnon, R.*
AU  - Michaux, A.*
AU  - Sarioglu, H.
AU  - Brown, N.*
AU  - Manning, G.*
AU  - Benotmane, M.A.*
AU  - Tapio, S.
AU  - Polanska, J.*
AU  - Bouffler, S.D.*
C1  - 48733
C2  - 41290
CY  - Albany
SP  - 40461-40480
TI  - Transcriptomic and proteomic analysis of mouse radiation-induced Acute Myeloid Leukaemia (AML).
JO  - Oncotarget
VL  - 7
IS  - 26
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Therapeutic irradiation of pediatric and adult patients can profoundly affect adult neurogenesis, and cognitive impairment manifests as a deficit in hippocampal-dependent functions. Age plays a major role in susceptibility to radiation, and younger children are at higher risk of cognitive decay when compared to adults. Cranial irradiation affects hippocampal neurogenesis by induction of DNA damage in neural progenitors, through the disruption of the neurogenic microenvironment, and defective integration of newborn neurons into the neuronal network. Our goal here was to assess cellular and molecular alterations induced by cranial X-ray exposure to low/moderate doses (0.1 and 2 Gy) in the hippocampus of mice irradiated at the postnatal ages of day 10 or week 10, as well as the dependency of these phenomena on age at irradiation. To this aim, changes in the cellular composition of the dentate gyrus, mitochondrial functionality, proteomic profile in the hippocampus, as well as cognitive performance were evaluated by a multidisciplinary approach. Our results suggest the induction of specific alterations in hippocampal neurogenesis, microvascular density and mitochondrial functions, depending on age at irradiation. A better understanding of how irradiation impairs hippocampal neurogenesis at low and moderate doses is crucial to minimize adverse effects of therapeutic irradiation, contributing also to radiation safety regulations.
AU  - Casciati, A.*
AU  - Dobos, K.*
AU  - Antonelli, F.*
AU  - Benedek, A.*
AU  - Kempf, S.J.
AU  - Bellés, M.*
AU  - Balogh, A.*
AU  - Tanori, M.*
AU  - Heredia, L.*
AU  - Atkinson, M.J.
AU  - von Toerne, C.
AU  - Azimzadeh, O.
AU  - Saran, A.*
AU  - Sáfrány, G.*
AU  - Benotmane, M.A.*
AU  - Linares-Vidal, M.V.*
AU  - Tapio, S.
AU  - Lumniczky, K.*
AU  - Pazzaglia, S.*
C1  - 48297
C2  - 39998
CY  - Albany
SP  - 28040-28058
TI  - Age-related effects of X-ray irradiation on mouse hippocampus.
JO  - Oncotarget
VL  - 7
IS  - 19
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Basic helix-loop-helix transcription factor Twist1 is a master regulator of Epithelial-Mesenchymal Transition (EMT), a cellular program implicated in different stages of development as well as metastatic dissemination of carcinomas. Here, we show that Twist1 requires TGF-beta type-I receptor (TGFBR1)-activation to bind an enhancer region of downstream effector ZEB1, thereby inducing ZEB1 transcription and EMT. When TGFBR1-phosphorylation is inhibited, Twist1 generates a distinct cell state characterized by collective invasion, simultaneous proliferation and expression of endothelial markers. By contrast, TGFBR1-activation directs Twist1 to induce stable mesenchymal transdifferentiation through EMT, thereby generating cells that display single-cell invasion, but lose their proliferative capacity. In conclusion, preventing Twist1-induced EMT by inhibiting TGFβ-signaling does not generally block acquisition of invasion, but switches mode from single-cell/non-proliferative to collective/proliferative. Together, these data reveal that transient Twist1-activation induces distinct cell states depending on signaling context and caution against the use of TGFβ-inhibitors as a therapeutic strategy to target invasiveness.
AU  - Dragoi, D.
AU  - Krattenmacher, A.
AU  - Mishra, V.K.*
AU  - Schmidt, J.
AU  - Kloos, U.
AU  - Meixner, L.K.
AU  - Hauck, S.M.
AU  - Buggenthin, F.
AU  - Schwartz, D.
AU  - Marr, C.
AU  - Johnsen, S.A.*
AU  - Scheel, C.
C1  - 48459
C2  - 41143
CY  - Albany
SP  - 30396-30407
TI  - Twist1 induces distinct cell states depending on TGFBR1-activation.
JO  - Oncotarget
VL  - 7
IS  - 21
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - We recently discovered mutation signatures reminiscent of BRCA deficiency in the vast majority of a set of primary osteosarcomas (OS). In the current study, we therefore investigated the sensitivity of a panel of OS cell lines to the poly(ADP)-ribose polymerase (PARP) inhibitor talazoparib alone and in combination with several chemotherapeutic drugs (i.e. temozolomide (TMZ), SN-38, doxorubicin, cisplatin, methotrexate (MTX), etoposide/carboplatin). Here, we identified an association between homologous recombination (HR) repair deficiency and the response of OS cell lines to talazoparib. All OS cell lines with molecular features characteristic of BRCA1/2 mutant tumors (so-called "BRCAness"), such as disruptive gains in PTEN or FANCD2 and/or losses of ATM, BAP1, BARD1 or CHEK2, were susceptible to talazoparib-induced reduction of cell viability (i.e. MG63, ZK-58,, SaOS-2 and MNNG-HOS). Consistent with their high sensitivity to talazoparib, MG63 and ZK-58 cells scored positive in a DNA-based measure of genomic instability (i.e. homologous recombination deficiency (HRD)-loss of heterozygosity (LOH) score). In contrast, U2OS cells that carry a heterozygous BRCA2 mutation and therefore most likely have one intact BRCA2 allele left proved to be resistant to talazoparib. Furthermore, we identified TMZ as the most potent chemotherapeutic drug together with talazoparib to synergistically reduce cell viability, as confirmed by calculation of combination index (CI) values, and to suppress long-term clonogenic survival. Mechanistically, talazoparib and TMZ cooperated to induce apoptotic cell death, as demonstrated by activation of BAX and BAK, loss of mitochondrial membrane potential (MMP), caspase activation, DNA fragmentation and caspase-dependent cell death. Genetic silencing of BAX and BAK or pharmacological inhibition of caspases by zVAD.fmk significantly rescued OS cells from talazoparib/TMZ-induced apoptosis. These findings have important implications for the development of novel treatment strategies using PARP inhibitors alone or together with chemotherapy in a subset of OS with features of BRCAness.
AU  - Engert, F.*
AU  - Kovac, M.*
AU  - Baumhoer, D.*
AU  - Nathrath, M.
AU  - Fulda, S.*
C1  - 49149
C2  - 41679
CY  - Orchard Park
SP  - 48794-48806
TI  - Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics.
JO  - Oncotarget
VL  - 8
IS  - 30
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor of the PI3K pathway. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.
AU  - Hensel, T.*
AU  - Giorgi, C.*
AU  - Schmidt, O.*
AU  - Calzada-Wack, J.
AU  - Neff, F.
AU  - Buch, T.*
AU  - Niggli, F.K.*
AU  - Schäfer, B.W.*
AU  - Burdach, S.*
AU  - Richter, G.H.*
C1  - 47459
C2  - 40584
SP  - 1451-1463
TI  - Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma.
JO  - Oncotarget
VL  - 7
IS  - 2
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - The triple-negative breast cancer (TNBC) is a very aggressive tumor type often occurring in young women and is associated with a bad prognosis for the patients. TNBC lacks established targets for breast cancer therapy, such as the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Therefore, novel therapeutic targets and strategies are needed for an improved treatment of this breast cancer subtype. TNBC and respective cell lines often overexpress proteins of the urokinase plasminogen activator system (uPAS) including uPA, its receptor uPAR and inhibitor PAI-1, which together with co-factors contribute to the malignancy of TNBC. Here, two novel interacting partners of uPAR, the cysteine-rich angiogenic inducer 61 (Cyr61) and the Y-box-binding protein 1 (YB-1) were identified and their differential expression demonstrated in TNBC cells as well as in tumors. In the TNBC cohort, both interactors significantly correlated with expression levels of cathepsin B, c-Met and the tumor grade. In addition, expression levels of Cyr61 significantly correlated with cathepsin D (p=0.03), insulin receptor (p≤0.001), insulin-like growth factor receptor 1 (IGF1R, p=0.015) and also with YB-1 (p=0.0004) levels. The interactions of uPAR with Cyr61 significantly correlated with expression levels of tumor-promoting biomarkers including plasminogen (p=0.0014), cathepsin B (p=0.032), c-Met (p=0.0192) as well as with the tumor grade (p=0.02). In multivariate survival analysis, YB-1 showed independent prognostic value (p=0.01). As the novel interacting partners, also together with uPAR, contribute to tumor progression and metastasis, both may be potential therapeutic targets in breast cancer.
AU  - Huber, M.
AU  - Falkenberg, N.
AU  - Hauck, S.M.
AU  - Priller, M.
AU  - Braselmann, H.
AU  - Feuchtinger, A.
AU  - Walch, A.K.
AU  - Schmitt, M.*
AU  - Aubele, M.
C1  - 48788
C2  - 41399
CY  - Albany
SP  - 44062-44075
TI  - Cyr61 and YB-1 are novel interacting partners of uPAR and elevate the malignancy of triple-negative breast cancer.
JO  - Oncotarget
VL  - 7
IS  - 28
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Chronic obstructive pulmonary disease (COPD) is related to an abnormal chronic inflammatory response of the lung to mainly cigarette smoke (CS) and the disease risk is increased in aged individuals. The source of this chronic inflammation is due to the repeated and progressive activation of immune cells. We hypothesize that in a chronic CS-induced mouse model, the predisposition to COPD pathogenesis in aged mice is characterized by an elevated immune response compared to young animals. We measured several characteristics of COPD in young and old mice (2 and 12 months of age) exposed to CS for 3 months. CS-exposed aged mice exhibited increased lung compliance (0.061 ± 0.008 vs. 0.055 ± 0.006 ml/cm H2O, p < 0.01), emphysema development (35.36 ± 0.71 vs. 25.31 ± 0.005 μm; p < 0.01) and airway remodeling (2.15 ± 0.37 vs. 1.09 ± 0.64 μm3/μm2; p < 0.01) compared to control animals, which was not seen in CS-exposed young mice. Quantification of lung tissue inflammation revealed a significantly greater volume of inducible bronchus-associated lymphoid tissue structures in aged mice after CS exposure (5.94 ± 2.89 vs. 2.37 ± 1.69 μm3/μm2; p < 0.01). Our results indicate that age-induced lung inflammation is further elevated after CS exposure in old mice, potentially via an age-induced change in immune cell susceptibility to CS thereby accelerating the pathophysiological hallmarks of COPD.
AU  - John-Schuster, G.
AU  - Günter, S.
AU  - Hager, K.
AU  - Conlon, T.M.
AU  - Eickelberg, O.
AU  - Yildirim, A.Ö.
C1  - 45500
C2  - 37339
CY  - Albany
SP  - 30068-30083
TI  - Inflammaging increases susceptibility to cigarette smoke-induced COPD.
JO  - Oncotarget
VL  - 7
IS  - 21
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer´s pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.
AU  - Kempf, S.J.
AU  - Janik, D.
AU  - Barjaktarovic, Z.
AU  - Braga-Tanaka III, I.*
AU  - Tanaka, S.*
AU  - Neff, F.
AU  - Saran, A.*
AU  - Larsen, M.R.*
AU  - Tapio, S.
C1  - 49692
C2  - 40878
CY  - Albany
SP  - 71817-71832
TI  - Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE-/- Alzheimer's mouse model.
JO  - Oncotarget
VL  - 7
IS  - 44
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Multimodal therapy of glioblastoma (GBM) reveals inter-individual variability in terms of treatment outcome. Here, we examined whether a miRNA signature can be defined for the a priori identification of patients with particularly poor prognosis.FFPE sections from 36 GBM patients along with overall survival follow-up were collected retrospectively and subjected to miRNA signature identification from microarray data. A risk score based on the expression of the signature miRNAs and cox-proportional hazard coefficients was calculated for each patient followed by validation in a matched GBM subset of TCGA. Genes potentially regulated by the signature miRNAs were identified by a correlation approach followed by pathway analysis.A prognostic 4-miRNA signature, independent of MGMT promoter methylation, age, and sex, was identified and a risk score was assigned to each patient that allowed defining two groups significantly differing in prognosis (p-value: 0.0001, median survival: 10.6 months and 15.1 months, hazard ratio = 3.8). The signature was technically validated by qRT-PCR and independently validated in an age- and sex-matched subset of standard-of-care treated patients of the TCGA GBM cohort (n=58). Pathway analysis suggested tumorigenesis-associated processes such as immune response, extracellular matrix organization, axon guidance, signalling by NGF, GPCR and Wnt. Here, we describe the identification and independent validation of a 4-miRNA signature that allows stratification of GBM patients into different prognostic groups in combination with one defined threshold and set of coefficients that could be utilized as diagnostic tool to identify GBM patients for improved and/or alternative treatment approaches.
AU  - Niyazi, M.
AU  - Pitea, A.
AU  - Mittelbronn, M.*
AU  - Steinbach, J.*
AU  - Sticht, C.*
AU  - Zehentmayr, F.*
AU  - Piehlmaier, D.
AU  - Zitzelsberger, H.
AU  - Ganswindt, U.
AU  - Rödel, C.*
AU  - Lauber, K.
AU  - Belka, C.
AU  - Unger, K.
C1  - 48928
C2  - 41514
CY  - Albany
SP  - 45764-45775
TI  - A 4-miRNA signature predicts the therapeutic outcome of glioblastoma.
JO  - Oncotarget
VL  - 7
IS  - 29
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Regulation of gene expression via microRNAs is known to promote the development of many types of cancer. In melanoma, miRNAs are globally up-regulated, and alterations of miRNA-processing enzymes have already been identified. However, mis-regulation of miRNA transport has not been analyzed in melanoma yet. We hypothesized that alterations in miRNA transport disrupt miRNA processing. Therefore, we investigated whether the pre-miRNA transporter Exportin-5 (XPO5) was involved in altered miRNA maturation and functional consequences in melanoma. We found that XPO5 is significantly over-expressed in melanoma compared with melanocytes. We showed enhanced XPO5 mRNA stability in melanoma cell lines which likely contributes to up-regulated XPO5 protein expression. In addition, we identified MEK signaling as a regulator of XPO5 expression in melanoma. Knockdown of XPO5 expression in melanoma cells led to decreased mature miRNA levels and drastic functional changes. Our data revealed that aberrant XPO5 expression is important for the maturation of miRNAs and the malignant behavior of melanoma cells. We suggest that the high abundance of XPO5 in melanoma leads to enhanced survival, proliferation and metastasis and thereby supports the aggressiveness of melanoma.
AU  - Ott, C.A.*
AU  - Linck, L.*
AU  - Kremmer, E.
AU  - Meister, G.*
AU  - Bosserhoff, A.K.*
C1  - 49320
C2  - 41736
CY  - Albany
SP  - 62292-62304
TI  - Induction of exportin-5 expression during melanoma development supports the cellular behavior of human malignant melanoma cells.
JO  - Oncotarget
VL  - 7
IS  - 38
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months in population-based studies. The main reason for tumor recurrence and progression is constitutive or acquired resistance to the standard of care of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ/RT→TMZ). Here, we investigated the role of microRNA (miRNA) alterations as mediators of alkylator resistance in glioblastoma cells. Using microarray-based miRNA expression profiling of parental and TMZ-resistant cultures of three human glioma cell lines, we identified a set of differentially expressed miRNA candidates. From these, we selected miR-138 for further functional analyses as this miRNA was not only upregulated in TMZ-resistant versus parental cells, but also showed increased expression in vivo in recurrent glioblastoma tissue samples after TMZ/RT→TMZ treatment. Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype. Altered sensitivity to apoptosis played only a minor role in this resistance mechanism. Instead, we identified the induction of autophagy to be regulated downstream of the miR-138/BIM axis and to promote cell survival following TMZ exposure. Our data thus define miR-138 as a glioblastoma cell survival-promoting miRNA associated with resistance to TMZ therapy in vitro and with tumor progression in vivo.
AU  - Stojcheva, N.*
AU  - Schechtmann, G.*
AU  - Sass, S.
AU  - Roth, P.*
AU  - Florea, A.M.*
AU  - Stefanski, A.*
AU  - Stühler, K.*
AU  - Wolter, M.*
AU  - Müller, N.S.
AU  - Theis, F.J.
AU  - Weller, M.G.*
AU  - Reifenberger, G.*
AU  - Happold, C.*
C1  - 47908
C2  - 39755
SP  - 12937-12950
TI  - MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM.
JO  - Oncotarget
VL  - 7
IS  - 11
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - It has historically been accepted that incorrectly repaired DNA double strand breaks (DSBs) are the principal lesions of importance regarding mutagenesis, and long-term biological effects associated with ionizing radiation. However, radiation may also cause dysregulation of epigenetic processes that can lead to altered gene function and malignant transformation, and epigenetic alterations are important causes of miRNAs dysregulation in cancer.Patched1 heterozygous (Ptch1+/-) mice, characterized by aberrant activation of the Sonic hedgehog (Shh) signaling pathway, are a well-known murine model of spontaneous and radiation-induced medulloblastoma (MB), a common pediatric brain tumor originating from neural granule cell progenitors (GCPs). The high sensitivity of neonatal Ptch1+/- mice to radiogenic MB is dependent on deregulation of the Ptch1 gene function. Ptch1 activates a growth and differentiation programme that is a strong candidate for regulation through the non-coding genome. Therefore we carried out miRNA next generation sequencing in ex vivo irradiated and control GCPs, isolated and purified from cerebella of neonatal WT and Ptch1+/- mice. We identified a subset of miRNAs, namely let-7 family and miR-17~92 cluster members, whose expression is altered in GCPs by radiation alone, or by synergistic interaction of radiation with Shh-deregulation. The same miRNAs were further validated in spontaneous and radiation-induced MBs from Ptch1+/- mice, confirming persistent deregulation of these miRNAs in the pathogenesis of MB.Our results support the hypothesis that miRNAs dysregulation is associated with radiosensitivity of GCPs and their neoplastic transformation in vivo.
AU  - Tanno, B.*
AU  - Babini, G.*
AU  - Leonardi, S.*
AU  - Giardullo, P.*
AU  - De Stefano, I.*
AU  - Pasquali, E.*
AU  - Ottolenghi, A.*
AU  - Atkinson, M.J.
AU  - Saran, A.*
AU  - Mancuso, M.*
C1  - 49488
C2  - 40701
CY  - Albany
SP  - 68253-68269
TI  - Ex vivo miRNome analysis in Ptch1+/- cerebellum granule cells reveals a subset of miRNAs involved in radiation-induced medulloblastoma.
JO  - Oncotarget
VL  - 7
IS  - 42
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Activation-induced cytidine deaminase (AID) initiates immunoglobulin diversification in germinal center B cells by targeted introduction of DNA damage. As aberrant nuclear AID action contributes to the generation of B cell lymphoma, the protein's activity is tightly regulated, e.g. by nuclear/cytoplasmic shuttling and nuclear degradation. In the present study, we asked whether DNA damage may affect regulation of the AID protein. We show that exogenous DNA damage that mainly activates base excision repair leads to prevention of proteasomal degradation of AID and hence its nuclear accumulation. Inhibitor as well as knockout studies indicate that activation of poly (ADP-ribose) polymerase (PARP) by DNA damaging agents promotes both phenomena. These findings suggest that PARP inhibitors influence DNA damage dependent AID regulation, with interesting implications for the regulation of AID function and chemotherapy of lymphoma.
AU  - Tepper, S.*
AU  - Jeschke, J.
AU  - Böttcher, K.*
AU  - Schmidt, A.*
AU  - Davari, K.*
AU  - Müller, P.*
AU  - Kremmer, E.
AU  - Hemmerich, P.*
AU  - Pfeil, I.
AU  - Jungnickel, B.
C1  - 47991
C2  - 39797
SP  - 13197-13208
TI  - PARP activation promotes nuclear AID accumulation in lymphoma cells.
JO  - Oncotarget
VL  - 7
IS  - 11
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Microarray analysis revealed genes of the posterior HOXD locus normally involved in bone formation to be over-expressed in primary Ewing sarcoma (ES). The expression of posterior HOXD genes was not influenced via ES pathognomonic EWS/ETS translocations. However, knock down of the dickkopf WNT signaling pathway inhibitor 2 (DKK2) resulted in a significant suppression of HOXD10, HOXD11 and HOXD13 while over-expression of DKK2 and stimulation with factors of the WNT signaling pathway such as WNT3a, WNT5a or WNT11 increased their expression. RNA interference demonstrated that individual HOXD genes promoted chondrogenic differentiation potential, and enhanced expression of the bone-associated gene RUNX2. Furthermore, HOXD genes increased the level of the osteoblast- and osteoclast-specific genes, osteocalcin (BGLAP) and platelet-derived growth factor beta polypeptide (PDGFB), and may further regulate endochondral bone development via induction of parathyroid hormone-like hormone (PTHLH). Additionally, HOXD11 and HOXD13 promoted contact independent growth of ES, while in vitro invasiveness of ES lines was enhanced by all 3 HOXD genes investigated and seemed mediated via matrix metallopeptidase 1 (MMP1). Consequently, knock down of HOXD11 or HOXD13 significantly suppressed lung metastasis in a xeno-transplant model in immune deficient mice, providing overall evidence that posterior HOXD genes promote clonogenicity and metastatic potential of ES.
AU  - von Heyking, K.*
AU  - Roth, L.C.*
AU  - Ertl, M.*
AU  - Schmidt, O.*
AU  - Calzada-Wack, J.
AU  - Neff, F.
AU  - Lawlor, E.R.*
AU  - Burdach, S.*
AU  - Richter, G.H.*
C1  - 48973
C2  - 41559
CY  - Albany
SP  - 41767-41780
TI  - The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma.
JO  - Oncotarget
VL  - 7
IS  - 27
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Long-term exposure to air pollution is associated with age-related diseases. We explored the association between accelerated biological aging and air pollution, a potential mechanism linking air pollution and health. We estimated long-term exposure to PM10, PM2.5, PM2.5 absorbance/black carbon (BC), and NOx via land-use regression models in individuals from the KORA F4 cohort. Accelerated biological aging was assessed using telomere length (TeloAA) and three epigenetic measures: DNA methylation age acceleration (DNAmAA), extrinsic epigenetic age acceleration (correlated with immune cell counts, EEAA), and intrinsic epigenetic age acceleration (independent of immune cell counts, IEAA). We also investigated sex-specific associations between air pollution and biological aging, given the published association between sex and aging measures. In KORA an interquartile range (0.97 µg/m3) increase in PM2.5 was associated with a 0.33 y increase in EEAA (CI = 0.01, 0.64; P = 0.04). BC and NOx (indicators or traffic exposure) were associated with DNAmAA and IEAA in women, while TeloAA was inversely associated with BC in men. We replicated this inverse BC-TeloAA association in the Normative Aging Study, a male cohort based in the USA. A multiple phenotype analysis in KORA F4 combining all aging measures showed that BC and PM10 were broadly associated with biological aging in men. Thus, we conclude that long-term exposure to air pollution is associated with biological aging measures, potentially in a sex-specific manner. However, many of the associations were relatively weak and further replication of overall and sex-specific associations is warranted.
AU  - Ward-Caviness, C.K.
AU  - Nwanaji-Enwerem, J.C.*
AU  - Wolf, K.
AU  - Wahl, S.
AU  - Colicino, E.*
AU  - Trevisi, L.*
AU  - Kloog, I.*
AU  - Just, A.C.*
AU  - Vokonas, P.*
AU  - Cyrys, J.
AU  - Gieger, C.
AU  - Schwartz, J.*
AU  - Baccarelli, A.A.*
AU  - Schneider, A.E.
AU  - Peters, A.
C1  - 49845
C2  - 40976
CY  - Albany
SP  - 74510-74525
TI  - Long-term exposure to air pollution is associated with biological aging.
JO  - Oncotarget
VL  - 7
IS  - 46
PB  - Impact Journals Llc
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - There is a need to develop new, more efficient therapies for head and neck cancer (HNSCC) patients. It is currently unclear whether defects in DNA repair genes play a role in HNSCCs' resistance to therapy. PARP1 inhibitors (PARPi) were found to be "synthetic lethal" in cancers deficient in BRCA1/2 with impaired homologous recombination. Since tumors rarely have these particular mutations, there is considerable interest in finding alternative determinants of PARPi sensitivity. Effectiveness of combined irradiation and PARPi olaparib was evaluated in ten HNSCC cell lines, subdivided into HR-proficient and HR-deficient cell lines using a GFP-based reporter assay. Both groups were equally sensitive to PARPi alone. Combined treatment revealed stronger synergistic interactions in the HR-deficient group. Because HR is mainly active in S-Phase, replication processes were analyzed. A stronger impact of treatment on replication processes (p = 0.04) and an increased number of radial chromosomes (p = 0.003) were observed in the HR-deficient group. We could show that radiosensitization by inhibition of PARP1 strongly correlates with HR competence in a replication-dependent manner. Our observations indicate that PARP1 inhibitors are promising candidates for enhancing the therapeutic ratio achieved by radiotherapy via disabling DNA replication processes in HR-deficient HNSCCs.
AU  - Wurster, S.*
AU  - Hennes, F.*
AU  - Parplys, A.C.*
AU  - Seelbach, J.I.*
AU  - Mansour, W.Y.*
AU  - Zielinski, A.*
AU  - Petersen, C.*
AU  - Clauditz, T.S.*
AU  - Münscher, A.*
AU  - Friedl, A.A.
AU  - Borgmann, K.*
C1  - 48261
C2  - 39981
SP  - 9732-9741
TI  - PARP1 inhibition radiosensitizes HNSCC cells deficient in homologous recombination by disabling the DNA replication fork elongation response.
JO  - Oncotarget
VL  - 7
IS  - 9
PY  - 2016
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - miR-221/-222 and components of the urokinase-type plasminogen activator system (uPAS) are associated with metastasis and poor prognosis in breast cancer, including the triple-negative subtype (TNBC). Modification of components of uPAS and involved miRNAs may contribute to targeted therapy for breast cancer patients. miR-221-/-222-overexpressing or miR-221-depleted cells were employed for qRT-PCR and Western blots to show associations of uPAR with miR-221/-222. To substantiate direct targeting of miR-221/-222 within 3' UTR of the uPAR isoform 2, in silico analysesand in vitro assays were conducted. Significant associations between miR-221 and uPAR isoform 2 expressions were observed at the mRNA and protein levels in breast cancer cells representing TNBC. For the first time, the uPAR isoform 2 was demonstrated as direct target for miR-221/-222. Inhibition of miR-221 reduced uPAR protein expression and expression of the tumor cell invasion markers vimentin and RHOC. These results demonstrate a direct and positive regulation of the secreted uPAR isoform 2 by miR-221, increasing its protein expression, a prerequisite for malignancy, while the other uPAR isoforms (1, 3 and 4) are indirectly regulated through miR-10b and miR-221/-222. By targeting uPAR isoforms and/or miRNA-221/-222, the diagnosis and therapy of breast cancer, in particular in TNBC, could be significantly improved.
AU  - Falkenberg, N.
AU  - Anastasov, N.
AU  - Schaub, A.
AU  - Radulovic, V.
AU  - Schmitt, M.*
AU  - Magdolen, V.*
AU  - Aubele, M.
C1  - 43273
C2  - 36280
SP  - 8103-8114
TI  - Secreted uPAR isoform 2 (uPAR7b) is a novel direct target of miR-221.
JO  - Oncotarget
VL  - 6
IS  - 10
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Objectives: Basaloid-squamous-carcinomas (BSCC) have been considered as aggressive variants of common squamous-cell-carcinomas (HNSCC). Recent studies demonstrated a different clinical course depending on the tumour site. The aim of the study is to analyze the histopathologic/clinical features of BSCC/HNSCC resolved by the HPV-status. Methods: We analysed the histopathologic/clinical features of BSCC (n=59) and HNSCC (n=981), subdivided due to the HPV status. Differences were analysed using Chi square, Fisher exact, and student's t-test. Survival rates were calculated by Kaplan-Meier and log-rank test. Prognostic variables were subsequently evaluated by Cox regression. Results: Our cohort was congruent with the literature regarding sex, age, metastases, and a predilection in the oropharynx. HNSCC/BSCC did not show a different disease-specific-survival. After UICC matching, univariate analysis revealed a better survival of UICC stage IVa BSCC compared to HNSCC (69% vs. 42%, p=0.022) that was associated with a better response to radio-chemotherapy (p = 0.009). These results referred to the high prevalence of HPV+ (86%) oropharyngeal BSCC. Subgroup analysis demonstrated a better survival of HPV+ oropharyngeal BSCC than HPV- BSCC (p=0.017). Conclusion: The clinical outcome in BSCC depends on the tumour site and HPV-status. Prospective studies have to evaluate the beneficial application of postoperative radio-chemotherapy in HPV+ BSCC.
AU  - Jacobi, C.*
AU  - Ayx, I.*
AU  - Fritsche, K.*
AU  - Piontek, G.*
AU  - Hoffmann, D.
AU  - Weirich, G.*
AU  - Knopf, A.*
C1  - 43611
C2  - 36669
SP  - 3462-3470
TI  - Potential impact of human papilloma virus on survival of basaloid squamous carcinoma of the head and neck.
JO  - Oncotarget
VL  - 6
IS  - 5
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - BMP7 is a growth factor playing pro- or anti-oncogenic roles in cancer in a cell type-dependent manner. We previously reported that the BMP7 gene is overexpressed in pheochromocytomas (PCCs) developing in MENX-affected rats and human patients. Here, analyzing a large cohort of PCC patients, we found that 72% of cases showed elevated levels of the BMP7 protein. To elucidate the role of BMP7 in PCC, we modulated its levels in PCC cell lines (overexpression in PC12, knockdown in MPC and MTT cells) and conducted functional assays. Active BMP signaling promoted cell proliferation, migration, and invasion, and sustained survival of MENX rat primary PCC cells. In PCC, BMP7 signals through the PI3K/AKT/mTOR pathway and causes integrin β1 up-regulation. Silencing integrin β1 in PC12 cells suppressed BMP7-mediated oncogenic features. Treatment of MTT cells with DMH1, a novel BMP antagonist, suppressed proliferation and migration. To verify the clinical applicability of our findings, we evaluated a dual PI3K/mTOR inhibitor (NVP-BEZ235) in MENX-affected rats in vivo. PCCs treated with NVP-BEZ235 had decreased proliferation and integrin β1 levels, and higher apoptosis. Altogether, BMP7 activates pro-oncogenic pathways in PCC. Downstream effectors of BMP7-mediated signaling may represent novel targets for treating progressive/inoperable PCC, still orphan of effective therapy.
AU  - Leinhäuser, I.
AU  - Richter, A.
AU  - Lee, M.S.
AU  - Höfig, I.
AU  - Anastasov, N.
AU  - Fend, F.*
AU  - Ercolino, T.*
AU  - Mannelli, M.*
AU  - Gimenez-Roqueplo, A.P.*
AU  - Robledo, M.*
AU  - de Krijger, R.R.*
AU  - Beuschlein, F.*
AU  - Atkinson, M.J.
AU  - Pellegata, N.S.
C1  - 46731
C2  - 37761
SP  - 39111-39126
TI  - Oncogenic features of the Bone Morphogenic Protein 7 (BMP7) in pheochromocytoma.
JO  - Oncotarget
VL  - 6
IS  - 36
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response.
AU  - Mancuso, M.*
AU  - Pasquali, E.*
AU  - Braga-Tanaka III, I.*
AU  - Tanaka, S.*
AU  - Pannicelli, A.*
AU  - Giardullo, P.*
AU  - Pazzaglia, S.*
AU  - Tapio, S.
AU  - Atkinson, M.J.
AU  - Saran, A.*
C1  - 46788
C2  - 37814
SP  - 31263-31271
TI  - Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation.
JO  - Oncotarget
VL  - 6
IS  - 31
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Survival of activated B cell-subtype (ABC) of diffuse large B cell lymphoma (DLBCL) is driven by chronic B cell receptor (BCR) signaling that activates the canonical NF-κB pathway. Inhibition of BTK by Ibrutinib has been shown to kill ABC DLBCL cells that carry activating mutations in the BCR adaptor CD79. However, mutations in BTK or in downstream components such as CARMA1/CARD11 can render lymphomas Ibrutinib resistant. Therefore, we assessed here the simultaneous inhibition of BTK and the protease MALT1 that acts downstream of CARMA1 and is essential for ABC DLBCL tumor growth. We show that in CD79 mutant cells BTK is a crucial upstream regulator of MALT1, but dispensable in CARMA1 mutant ABC DLBCL. Combined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of NF-κB pro-survival factors. Thereby, combinatorial Ibrutinib and S-Mepazine treatment enhanced killing of CD79 mutant ABC DLBCL cells. Moreover, while expression of oncogenic CARMA1 in CD79 mutant cells conferred Ibrutinib resistance, double mutant cells were still sensitive to MALT1 inhibition by S-Mepazine. Thus, based on the genetic background combinatorial BTK and MALT1 inhibition may improve effectiveness of therapeutic treatment and reduce the chances for the development of drug resistances.
AU  - Nagel, D.
AU  - Bognar, M.
AU  - Eitelhuber, A.C.
AU  - Kutzner, K.
AU  - Vincendeau, M.
AU  - Krappmann, D.
C1  - 47163
C2  - 39124
SP  - 42232-42242
TI  - Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma.
JO  - Oncotarget
VL  - 6
IS  - 39
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.
AU  - Ribi, S.*
AU  - Baumhoer, D.
AU  - Lee, K.*
AU  - Edison*
AU  - Teo, A.S.*
AU  - Madan, B.*
AU  - Zhang, K.*
AU  - Kohlmann, W.K.*
AU  - Yao, F.*
AU  - Lee, W.H.*
AU  - Hoi, Q.*
AU  - Cai, S.W.*
AU  - Woo, X.Y.*
AU  - Tan, P.L.*
AU  - Jundt, G.*
AU  - Smida, J.
AU  - Nathrath, M.
AU  - Sung, W.K.*
AU  - Schiffman, J.D.*
AU  - Virshup, D.M.*
AU  - Hillmer, A.M.*
C1  - 44010
C2  - 36689
SP  - 7727-7740
TI  - TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.
JO  - Oncotarget
VL  - 6
IS  - 10
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - In spite of development of molecular therapeutics, multiple myeloma (MM) is fatal in most cases. CD38 is a promising target for selective treatment of MM. We tested radioimmunoconjugates consisting of the α-emitter 213Bi coupled to an anti-CD38 MAb in preclinical treatment of MM. Efficacy of 213Bi-anti-CD38-MAb was assayed towards different MM cell lines with regard to induction of DNA double-strand breaks, induction of apoptosis and initiation of cell cycle arrest. Moreover, mice bearing luciferase-expressing MM xenografts were treated with 213Bi-anti-CD38-MAb. Therapeutic efficacy was monitored by bioluminescence imaging, overall survival and histology. 213Bi-anti-CD38-MAb treatment induced DNA damage which did not result in activation of the G2 DNA-damage-response checkpoint, but instead in mitotic arrest and subsequent mitotic catastrophe. The anti-tumor effect of 213Bi-anti-CD38-MAb correlated with the expression level of CD38 in each MM cell line. In myeloma xenografts, treatment with 213Bi-anti-CD38-MAb suppressed tumor growth via induction of apoptosis in tumor tissue and significantly prolonged survival compared to controls. The major organ systems did not show any signs of 213Bi-induced toxicity. Preclinical treatment of MM with 213Bi-anti-CD38-MAb turned out as an effective therapeutic option.
AU  - Teiluf, K.*
AU  - Seidl, C.*
AU  - Blechert, B.*
AU  - Gaertner, F.C.*
AU  - Gilbertz, K.P.*
AU  - Fernandez, V.*
AU  - Bassermann, F.*
AU  - Endell, J.*
AU  - Boxhammer, R.*
AU  - Leclair, S.*
AU  - Vallon, M.*
AU  - Aichler, M.
AU  - Feuchtinger, A.
AU  - Bruchertseifer, F.*
AU  - Morgenstern, A.*
AU  - Essler, M.*
C1  - 43087
C2  - 36027
SP  - 4692-4703
TI  - α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma.
JO  - Oncotarget
VL  - 6
IS  - 7
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypicallyestimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P=7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O. R.=1.12; P=3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O. R.=1.14; 95% C. I.=1.03-1.28) and TERT (O. R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O. R.=1.18; 95% C. I.=1.05-1.33) and CTC1 (O. R.=1.14; 95% C. I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.
AU  - Walsh, K.M.*
AU  - Codd, V.*
AU  - Rice, T.*
AU  - Nelson, C.P.*
AU  - Smirnov, I.V.*
AU  - McCoy, L.S.*
AU  - Hansen, H.M.*
AU  - Elhauge, E.*
AU  - Ojha, J.*
AU  - Francis, S.S.*
AU  - Madsen, N.R.*
AU  - Bracci, P.M.*
AU  - Pico, A.R.*
AU  - Molinaro, A.M.*
AU  - Tihan, T.*
AU  - Berger, M.S.*
AU  - Chang, S.M.*
AU  - Prados, M.D.*
AU  - Jenkins, R.B.*
AU  - Wiemels, J.L.*
AU  - Samani, N.J.*
AU  - Wiencke, J.K.*
AU  - Wrensch, M.R.*
AU  - ENGAGE Consortium Telomere Group (Albrecht, E.
AU  - Gieger, C.
AU  - Klopp, N.
AU  - Peters, A.
AU  - Wichmann, H.-E.)
C1  - 48122
C2  - 39937
CY  - Albany
SP  - 42468-42477
TI  - Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.
JO  - Oncotarget
VL  - 6
IS  - 40
PB  - Impact Journals Llc
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Quantification of tumor necrosis in cancer patients is of diagnostic value as the amount of necrosis is correlated with disease prognosis and it could also be used to predict early efficacy of anti-cancer treatments. In the present study, we identified two near infrared fluorescent (NIRF) carboxylated cyanines, HQ5 and IRDye 800CW (800CW), which possess strong necrosis avidity. In vitro studies showed that both dyes selectively bind to cytoplasmic proteins of dead cells that have lost membrane integrity. Affinity for cytoplasmic proteins was confirmed using quantitative structure activity relations modeling. In vivo results, using NIRF and optoacoustic imaging, confirmed the necrosis avid properties of HQ5 and 800CW in a mouse 4T1 breast cancer tumor model of spontaneous necrosis. Finally, in a mouse EL4 lymphoma tumor model, already 24 h post chemotherapy, a significant increase in 800CW fluorescence intensity was observed in treated compared to untreated tumors. In conclusion, we show, for the first time, that the NIRF carboxylated cyanines HQ5 and 800CW possess strong necrosis avid properties in vitro and in vivo. When translated to the clinic, these dyes may be used for diagnostic or prognostic purposes and for monitoring in vivo tumor response early after the start of treatment.
AU  - Xie, B.*
AU  - Stammes, M.A.*
AU  - van Driel, P.B.*
AU  - Cruz, L.J.*
AU  - Knol-Blankevoort, V.T.*
AU  - Löwik, M.A.*
AU  - Mezzanotte, L.*
AU  - Que, I.*
AU  - Chan, A.*
AU  - van den Wijngaard, J.P.*
AU  - Siebes, M.*
AU  - Gottschalk, S.
AU  - Razansky, D.
AU  - Ntziachristos, V.
AU  - Keereweer, S.*
AU  - Horobin, R.W.*
AU  - Hoehn, M.*
AU  - Kaijzel, E.L.*
AU  - van Beek, E.R.*
AU  - Snoeks, T.J.*
AU  - Löwik, C.W.*
C1  - 47274
C2  - 39326
SP  - 39036-39049
TI  - Necrosis avid near infrared fluorescent cyanines for imaging cell death and their use to monitor therapeutic efficacy in mouse tumor models.
JO  - Oncotarget
VL  - 6
IS  - 36
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Prognosis for patients suffering from T-ALL is still very poor and new strategies for T-ALL treatment are urgently needed. Our study shows potent anti-leukemic effects of the myxobacterial V-ATPase inhibitor Archazolid A. Archazolid A reduced growth and potently induced death of leukemic cell lines and human leukemic samples. By inhibiting lysosomal acidification, Archazolid A blocked activation of the Notch pathway, however, this was not the mechanism of V-ATPase inhibition relevant for cell death induction. In fact, V-ATPase inhibition by Archazolid A decreased the anti-apoptotic protein survivin. As underlying mode of action, this work is in line with recent studies from our group demonstrating that Archazolid A induced S-phase cell cycle arrest by interfering with the iron metabolism in leukemic cells. Our study provides evidence for V-ATPase inhibition as a potential new therapeutic option for T-ALL.
AU  - Zhang, S.*
AU  - Schneider, L.S.*
AU  - Vick, B.
AU  - Grunert, M.
AU  - Jeremias, I.
AU  - Menche, D.*
AU  - Müller, R.*
AU  - Vollmar, A.M.*
AU  - Liebl, J.*
C1  - 47668
C2  - 39578
SP  - 43508-43528
TI  - Anti-leukemic effects of the V-ATPase inhibitor Archazolid A.
JO  - Oncotarget
VL  - 6
IS  - 41
PY  - 2015
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Neoadjuvant platin-based therapy is accepted as a standard therapy for advanced esophageal adenocarcinoma (EAC). Patients who respond have a better survival prognosis, but still a significant number of responder patients die from tumor recurrence. Molecular markers for prognosis in neoadjuvantly treated EAC patients have not been identified yet. We investigated the epidermal growth factor receptor (EGFR) in prognosis and chemotherapy resistance in these patients. Two EAC patient cohorts, either treated by neoadjuvant cisplatin-based chemotherapy followed by surgery (n=86) or by surgical resection (n=46) were analyzed for EGFR protein expression and gene copy number. Data were correlated with clinical and histopathological response, disease-free and overall survival. In case of EGFR overexpression, the prognosis for neoadjuvant chemotherapy responders was poor as in non-responders. Responders had a significantly better disease-free survival than non-responders only if EGFR expression level (p=0.0152) or copy number (p=0.0050) was low. Comparing neoadjuvantly treated patients and primary resection patients, tumors of non-responder patients more frequently exhibited EGFR overexpression, providing evidence that EGFR is a factor for indicating chemotherapy resistance. EGFR overexpression and gene copy number are independent adverse prognostic factors for neoadjuvant chemotherapy-treated EAC patients, particularly for responders. Furthermore, EGFR overexpression is involved in resistance to cisplatin-based neoadjuvant chemotherapy.
AU  - Aichler, M.
AU  - Motschmann, M.
AU  - Jütting, U.
AU  - Luber, B.*
AU  - Becker, K.*
AU  - Ott, K.*
AU  - Lordick, F.*
AU  - Langer, R.*
AU  - Feith, M.*
AU  - Siewert, J.R.*
AU  - Walch, A.K.
C1  - 32171
C2  - 34977
SP  - 6620-6632
TI  - Epidermal Growth Factor Receptor (EGFR) is an independent adverse prognostic factor in esophageal adenocarcinoma patients treated with cisplatin-based neoadjuvant chemotherapy.
JO  - Oncotarget
VL  - 5
IS  - 16
PY  - 2014
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.
AU  - Alachkar, H.*
AU  - Mutonga, M.B.*
AU  - Metzeler, K.H.
AU  - Fulton, N.*
AU  - Malnassy, G.*
AU  - Herold, T.
AU  - Spiekermann, K.
AU  - Bohlander, S.K.*
AU  - Hiddemann, W.
AU  - Matsuo, Y.*
AU  - Stock, W.*
AU  - Nakamura, Y.*
C1  - 34361
C2  - 35267
SP  - 12371-12382
TI  - Preclinical efficacy of Maternal Embryonic Leucine-zipper Kinase (MELK) inhibition in acute myeloid leukemia.
JO  - Oncotarget
VL  - 5
IS  - 23
PY  - 2014
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Tumor metastasis is the major cause of mortality and morbidity in most solid cancers. A growing body of evidence suggests that the epithelial-to-mesenchymal transition (EMT) plays a central role during tumor metastasis and frequently imparts a stem cell-like phenotype and therapeutic resistance to tumor cells. The induction of EMT is accompanied by a dynamic reprogramming of the epigenome involving changes in DNA methylation and several post-translational histone modifications. These changes in turn promote the expression of mesenchymal genes or repress those associated with an epithelial phenotype. Importantly, in order for metastatic colonization and the formation of macrometastases to occur, tumor cells frequently undergo a reversal of EMT referred to as the mesenchymal-to-epithelial transition (MET). Thus, a high degree of epigenetic plasticity is required in order to induce and reverse EMT during tumor progression. In this review, we describe various epigenetic regulatory mechanisms employed by tumor cells during EMT and elaborate on the importance of the histone code in controlling both the expression and activity of EMTassociated transcription factors. We propose that a more thorough understanding of the epigenetic mechanisms controlling EMT may provide new opportunities which may be harnessed for improved and individualized cancer therapy based on defined molecular mechanisms.
AU  - Bedi, U.*
AU  - Kumar Mishra, V.*
AU  - Wasilewski, D.
AU  - Scheel, C.
AU  - Johnsen, S.A.*
C1  - 31244
C2  - 34273
SP  - 2016-2029
TI  - Epigenetic plasticity: A central regulator of epithelial-tomesenchymal transition in cancer.
JO  - Oncotarget
VL  - 5
IS  - 8
PY  - 2014
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells.
AU  - Keitel, U.*
AU  - Scheel, A.*
AU  - Thomale, J.*
AU  - Halpape, R.*
AU  - Kaulfuß, S.*
AU  - Scheel, C.
AU  - Dobbelstein, M.*
C1  - 42902
C2  - 35810
SP  - 11778-11791
TI  - Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation.
JO  - Oncotarget
VL  - 5
IS  - 23
PY  - 2014
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR-IL-6-STAT3 signaling loop. Inhibition of the AHR-IL-6-STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients.
AU  - Litzenburger, U.M.*
AU  - Opitz, C.A.*
AU  - Sahm, F.*
AU  - Rauschenbach, K.J.*
AU  - Trump, S.*
AU  - Winter, M.*
AU  - Ott, M.*
AU  - Ochs, K.*
AU  - Lutz, C.*
AU  - Liu, X.*
AU  - Anastasov, N.
AU  - Lehmann, I.*
AU  - Höfer, T.*
AU  - von Deimling, A.*
AU  - Wick, W.*
AU  - Platten, M.*
C1  - 30910
C2  - 34007
SP  - 1038-1051
TI  - Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR.
JO  - Oncotarget
VL  - 5
IS  - 4
PY  - 2014
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches.
AU  - Neumann, M.*
AU  - Vosberg, S.
AU  - Schlee, C.*
AU  - Heesch, S.*
AU  - Schwartz, S.*
AU  - Gökbuget, N.*
AU  - Hoelzer, D.*
AU  - Graf, A.*
AU  - Krebs, S.*
AU  - Bartram, I.*
AU  - Blum, H.*
AU  - Brüggemann, M.*
AU  - Hecht, J.*
AU  - Bohlander, S.K.
AU  - Greif, P.A.
AU  - Baldus, C.D.*
C1  - 43123
C2  - 36299
SP  - 2754-2766
TI  - Mutational spectrum of adult T-ALL.
JO  - Oncotarget
VL  - 6
IS  - 5
PY  - 2014
SN  - 1949-2553
ER  - 

TY  - JOUR
AU  - Willimsky, G.*
AU  - Protzer, U.
AU  - Knolle, P.*
AU  - Heikenwälder, M.
C1  - 27252
C2  - 32586
SP  - 1117-1118
TI  - Adoptive T-cell therapy to treat liver cancer: Is the liver microenvironment key?
JO  - Oncotarget
VL  - 4
IS  - 8
PB  - Impact Journals LLC
PY  - 2013
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Metastasis is a multistep process characterized by the ability of tumor cells to "communicate" and to interact with their microenvironment to establish tumors in distant organs. A significant proportion of the metastatic microenvironment consists of leukocytes, mostly of the innate immune system, contributing to tumor invasion and outgrowth.
AU  - Hoos, A.*
AU  - Wolf, M.J.*
AU  - Bauer, J.
AU  - Borsig, L.*
AU  - Heikenwälder, M.
C1  - 10890
C2  - 30446
SP  - 919-920
TI  - Endothelial chemokine receptors as facilitators of tumor cell extravasation?
JO  - Oncotarget
VL  - 3
IS  - 9
PB  - Impact Journals LLC
PY  - 2012
SN  - 1949-2553
ER  - 

TY  - JOUR
AU  - Krappmann, D.
C1  - 11610
C2  - 30714
SP  - 1489-1490
TI  - Attacking MALT1 for ABC-DLBCL therapy.
JO  - Oncotarget
VL  - 3
IS  - 12
PB  - Impact Journals LLC
PY  - 2012
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Predicting the clinical course of osteosarcoma patients is a crucial prerequisite for a better treatment stratification in these highly aggressive neoplasms of bone. In search of new and reliable biomarkers we recently identified cysteine-rich intestinal protein 1 (CRIP1) to have significant prognostic impact in gastric cancer and therefore decided to investigate its role also in osteosarcoma. For this purpose we analyzed 223 pretherapeutic and well characterized osteosarcoma samples for their immunohistochemical expression of CRIP1 and correlated our findings with clinico-pathological parameters including follow‑up, systemic spread and response to chemotherapy. Interestingly and contrarily to gastric cancer, we found CRIP1 expression more frequently in patients with long‑term survival (10-year survival 73% in positive vs. 54% in negative cases, p = 0.0433) and without metastases (p = 0.0108) indicating a favorable prognostic effect. CRIP1 therefore seems to represent a promising new biomarker in osteosarcoma patients which should be considered for a prospective validation.
AU  - Baumhoer, D.
AU  - Elsner, M.
AU  - Smida, J.
AU  - Zillmer, S.
AU  - Rauser, S.
AU  - Schoene, C.
AU  - Balluff, B.
AU  - Bielack, S.*
AU  - Jundt, G.*
AU  - Walch, A.K.
AU  - Nathrath, M.
C1  - 7196
C2  - 29541
SP  - 970-975
TI  - CRIP1 expression is correlated with a favorable outcome and less metastases in osteosarcoma patients.
JO  - Oncotarget
VL  - 2
IS  - 12
PB  - Impact Journals LLC
PY  - 2011
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - Since its first description more than 30 years ago p53 has become a paradigm for a protein with versatile functions. P53 sensitizes a large variety of genetic alterations and has been entitled the guardian of the genome. Stabilization of p53 upon DNA damage is accompanied by a complex pattern of modifications, which ascertain the cellular response either in the direction of a reversible or irreversible cell cycle arrest or programmed cell death. More recently it became evident that p53 also responds to non-genotoxic cell stress, in particular if ribosome biogenesis is affected.
AU  - Hölzel, M.
AU  - Burger, K.
AU  - Mühl, B.
AU  - Orban, M.
AU  - Kellner, M.
AU  - Eick, D.
C1  - 4783
C2  - 27626
SP  - 43-47
TI  - The tumor suppressor p53 connects ribosome biogenesis to cell cycle control: A double-edged sword.
JO  - Oncotarget
VL  - 1
IS  - 1
PB  - Impact Journals LLC
PY  - 2010
SN  - 1949-2553
ER  - 

TY  - JOUR
AB  - There is growing evidence that chronic inflammatory processes are involved in triggering the sequence from chronic liver injury to liver fibrosis, ultimately leading to liver cancer. In the last years this process has been recapitulated in a growing number of different mouse models. However, it has remained unclear whether and how these mouse models reflect the clinical reality of human hepatocellular carcinoma (HCC). Research with animal models but also human liver specimens has indicated that the NF-κB signaling pathway might withhold a crucial function in the mediation of chronic hepatic inflammation and the transition to HCC in humans. However, previous studies led to divergent and partly conflicting results with regards to the functional role of NF-κB in hepatocarcinogenesis. Here, we discuss a new genetic mouse model for HCC, the liver-specific TAK1 knockout mouse, which lacks the NF-κB activating kinase TAK1 specifically in parenchymal liver cells. Molecular findings in this mouse model and their possible significance for chemopreventive strategies against HCC are compared to other murine HCC models.
AU  - Vucur, M.*
AU  - Roderburg, C.*
AU  - Bettermann, K.*
AU  - Tacke, F.*
AU  - Heikenwälder, M.
AU  - Trautwein, C.*
AU  - Luedde, T.*
C1  - 23832
C2  - 31490
SP  - 373-378
TI  - Mouse models of hepatocarcinogenesis: What can we learn for the prevention of human hepatocellular carcinoma?
JO  - Oncotarget
VL  - 1
IS  - 5
PB  - Impact Journal LLC
PY  - 2010
SN  - 1949-2553
ER  -