TY  - JOUR
AB  - Cancer cachexia (Ccx) is a complex metabolic condition characterized by pronounced muscle and fat wasting, systemic inflammation, weakness and fatigue. Up to 30% of cancer patients succumb directly to Ccx, yet therapies that effectively address this perturbed metabolic state are rare. In recent decades, several characteristics of Ccx have been established in mice and humans, of which we here highlight adipose tissue dysfunction, muscle wasting and systemic inflammation, as they are directly linked to biomarker discovery. To counteract cachexia pathogenesis as early as possible and mitigate its detrimental impact on anti-cancer treatments, identification and validation of clinically endorsed biomarkers assume paramount importance. Ageing was recently shown to affect both the validity of Ccx biomarkers and Ccx development, but the underlying mechanisms are still unknown. Thus, unravelling the intricate interplay between ageing and Ccx can help to counteract Ccx pathogenesis and tailor diagnostic and treatment strategies to individual needs.
AU  - Geppert, J.
AU  - Rohm, M.
C1  - 70110
C2  - 55429
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Cancer cachexia: Biomarkers and the influence of age.
JO  - Mol. Oncol.
PB  - Wiley
PY  - 2024
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - Head and neck squamous cell carcinomas (HNSCCs) have poor clinical outcome owing to therapy resistance and frequent recurrences that are among others attributable to tumor cells in partial epithelial-to-mesenchymal transition (pEMT). We compared side-by-side software-based and visual quantification of immunohistochemistry (IHC) staining of epithelial marker EpCAM and EMT regulator Slug in n = 102 primary HNSCC to assess optimal analysis protocols. IHC scores incorporated expression levels and percentages of positive cells. Digital and visual evaluation of membrane-associated EpCAM yielded correlating scorings, whereas visual evaluation of nuclear Slug resulted in significantly higher overall scores. Multivariable Cox proportional hazard analysis defined the median EpCAM expression levels resulting from visual quantification as an independent prognostic factor of overall survival. Slug expression levels resulting from digital quantification were an independent prognostic factor of recurrence-free survival, locoregional recurrence-free survival, and disease-specific survival. Hence, we propose to use visual assessment for the membrane-associated EpCAM protein, whereas nuclear protein Slug assessment was more accurate following digital measurement.
AU  - Schinke, H.*
AU  - Heider, T.
AU  - Herkommer, T.
AU  - Simon, F.*
AU  - Blancke Soares, A.*
AU  - Kranz, G.*
AU  - Samaga, D.
AU  - Dajka, L.
AU  - Feuchtinger, A.
AU  - Walch, A.K.
AU  - Valeanu, L.*
AU  - Walz, C.*
AU  - Kirchner, T.*
AU  - Canis, M.*
AU  - Baumeister, P.
AU  - Belka, C.
AU  - Maihöfer, C.
AU  - Marschner, S.
AU  - Pflugradt, U.
AU  - Ganswindt, U.*
AU  - Hess J.
AU  - Zitzelsberger, H.
AU  - Gires, O.
C1  - 60881
C2  - 49712
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1040-1053
TI  - Digital scoring of EpCAM and slug expression as prognostic markers in head and neck squamous cell carcinomas.
JO  - Mol. Oncol.
VL  - 15
IS  - 4
PB  - Wiley
PY  - 2021
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - Partial epithelial-to-mesenchymal transition (pEMT) contributes to cellular heterogeneity that is associated with nodal metastases and unfavorable clinical parameters in head and neck squamous cell carcinomas (HNSCCs). We developed a single-cell RNA sequencing signature-based pEMT quantification through cell type-dependent deconvolution of bulk RNA sequencing and microarray data combined with single-sample scoring of molecular phenotypes (Singscoring). Clinical pEMT-Singscores served as molecular classifiers in multivariable Cox proportional hazard models and high scores prognosticated poor overall survival and reduced response to irradiation as independent parameters in large HNSCC cohorts [The Cancer Genome Atlas (TCGA), MD Anderson Cancer Centre (MDACC), Fred Hutchinson Cancer Research Center (FHCRC)]. Differentially expressed genes confirmed enhanced cell motility and reduced oxidative phosphorylation and epithelial differentiation in pEMThigh patients. In patients and cell lines, the EMT transcription factor SLUG correlated most strongly with pEMT-Singscores and promoted pEMT, enhanced invasion, and resistance to irradiation in vitro. SLUG protein levels in HNSCC predicted disease-free survival, and its peripheral expression at the interphase to the tumor microenvironment was significantly increased in relapsing patients. Hence, pEMT-Singscores represent a novel risk predictor for HNSCC stratification regarding clinical outcome and therapy response that is partly controlled by SLUG.
AU  - Schinke, H.*
AU  - Pan, M.*
AU  - Akyol, M.*
AU  - Zhou, J.*
AU  - Shi, E.*
AU  - Kranz, G.*
AU  - Libl, D.*
AU  - Quadt, T.*
AU  - Simon, F.*
AU  - Canis, M.
AU  - Baumeister, P.
AU  - Gires, O.
C1  - 62842
C2  - 51097
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - SLUG-related partial epithelial-to-mesenchymal transition is a transcriptomic prognosticator of head and neck cancer survival.
JO  - Mol. Oncol.
PB  - Wiley
PY  - 2021
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - Mast cells are a major component of the immune microenvironment in tumour tissues and modulate tumour progression by releasing pro-tumorigenic and antitumorigenic molecules. Regarding the impact of mast cells on the outcomes of patients with lung adenocarcinoma (LUAD) patient, several published studies have shown contradictory results. Here, we aimed at elucidating the role of mast cells in early-stage LUAD. We found that high mast cell abundance was correlated with prolonged survival in early-stage LUAD patients. The mast cell-related gene signature and gene mutation data sets were used to stratify early-stage LUAD patients into two molecular subtypes (subtype 1 and subtype 2). The neural network-based framework constructed with the mast cell-related signature showed high accuracy in predicting response to immunotherapy. Importantly, the prognostic mast cell-related signature predicted the survival probability and the potential relationship between TP53 mutation, c-MYC activation and mast cell activities. The meta-analysis confirmed the prognostic value of the mast cell-related gene signature. In summary, this study might improve our understanding of the role of mast cells in early-stage LUAD and aid in the development of immunotherapy and personalized treatments for early-stage LUAD patients.
AU  - Bao, X.
AU  - Shi, R.*
AU  - Zhao, T.
AU  - Wang, Y.*
C1  - 58592
C2  - 48209
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 917-932
TI  - Mast cell-based molecular subtypes and signature associated with clinical outcome in early-stage lung adenocarcinoma.
JO  - Mol. Oncol.
VL  - 14
IS  - 5
PB  - Wiley
PY  - 2020
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - Pancreatic ductal adenocarcinoma (PDAC) will soon belong to the top three cancer killers. The only approved specific PDAC therapy targets the epidermal growth factor receptor (EGFR). Although EGFR is a crucial player in PDAC development, EGFR-based therapy is disappointing. In this study, we evaluated the role of the EGFR ligand betacellulin (BTC) in PDAC. The expression of BTC was investigated in human pancreatic cancer specimen. Then, we generated a BTC knockout mouse model by CRISPR/Cas9 technology and a BTC overexpression model. Both models were crossed with the Ptf1a(Cre/+);KRAS(G12D/+) (KC) mouse model (B-/-KC or BKC, respectively). In addition, EGFR, ERBB2, and ERBB4 were investigated by the pancreas-specific deletion of each receptor using the Cre-loxP system. Tumor initiation and progression were analyzed in all mouse lines, and the underlying molecular biology of PDAC was investigated at different time points. BTC is expressed in human and murine PDAC. B-/-KC mice showed a decelerated PDAC progression, associated with decreased EGFR activation. BKC mice developed severe PDAC with a poor survival rate. The dramatically increased BTC-mediated tumor burden was EGFR-dependent, but also ERBB4 and ERBB2 were involved in PDAC development or progression, as depletion of EGFR, ERBB2, or ERBB4 significantly improved the survival rate of BTC-mediated PDAC. BTC increases PDAC tumor burden dramatically by enhanced RAS activation. EGFR signaling, ERBB2 signaling, and ERBB4 signaling are involved in accelerated PDAC development mediated by BTC indicating that targeting the whole ERBB family, instead of a single receptor, is a promising strategy for the development of future PDAC therapies.
AU  - Hedegger, K.*
AU  - Algül, H.*
AU  - Lesina, M.*
AU  - Blutke, A.
AU  - Schmid, R.M.*
AU  - Schneider, M.R.*
AU  - Dahlhoff, M.*
C1  - 59200
C2  - 48660
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1653-1669
TI  - Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice.
JO  - Mol. Oncol.
VL  - 14
IS  - 8
PB  - Wiley
PY  - 2020
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - Nonsense-mediated decay (NMD) proteins are responsible for the surveillance and degradation of aberrant RNAs. Suppressor with morphogenetic effect on genitalia 7 (SMG7) is an NMD complex protein and a regulator of tumor necrosis factor (TNF)-induced extrinsic apoptosis; however, this unique function has not been explored in detail. In this study, we show that loss ofSmg7leads to unrestricted expression of long noncoding RNAs (lncRNAs) in addition to NMD targets. Functional analysis ofSmg7(-/-)cells showed downregulation of the tumor suppressor cylindromatosis (CYLD) and diminished caspase activity, thereby switching cells to nuclear factor-kappa B (NF-kappa B)-mediated protection. This positive relationship betweenSMG7andCYLDwas found to be widely conserved in human cancer cell lines and renal carcinoma samples from The Cancer Genome Atlas. In addition to CYLD suppression, upregulation of lncRNAsPvt1andAdapt33rendered cells resistant to TNF, while pharmacologic inhibition of NF-kappa B inPvt1-overexpressing TNF-resistant cells andSmg7-deficient spheroids re-established TNF-induced lethality. Thus, loss of SMG7 decouples regulation of two separate oncogenic factors with cumulative downstream effects on the NF-kappa B pathway. The data highlight a novel and specific regulation of oncogenic factors by SMG7 and pinpoint a composite tumor suppressor role in response to TNF.
AU  - Yang, L.
AU  - Kraft, V.
AU  - Pfeiffer, S.
AU  - Merl-Pham, J.
AU  - Bao, X.
AU  - An, Y.*
AU  - Hauck, S.M.
AU  - Schick, J.
C1  - 59534
C2  - 48833
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 2420-2435
TI  - Nonsense-mediated decay factor SMG7 sensitizes cells to TNF alpha-induced apoptosis via CYLD tumor suppressor and the noncoding oncogenePvt1.
JO  - Mol. Oncol.
VL  - 14
IS  - 10
PB  - Wiley
PY  - 2020
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET-amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.
AU  - Keller, S.*
AU  - Zwingenberger, G.*
AU  - Ebert, K.*
AU  - Hasenauer, J.
AU  - Wasmuth, J.*
AU  - Maier, D.*
AU  - Haffner, I.*
AU  - Schierle, K.*
AU  - Weirich, G.*
AU  - Luber, B.*
C1  - 52837
C2  - 44197
SP  - 441-462
TI  - Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines.
JO  - Mol. Oncol.
VL  - 12
IS  - 4
PY  - 2018
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - Previously, we have shown that copy number gain of the chromosomal band 16q24.3 is associated with impaired clinical outcome of radiotherapy-treated head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify a prognostic mRNA signature from genes located on 16q24.3 in radio(chemo)therapy-treated HNSCC patients of the TCGA (The Cancer Genome Atlas, n = 99) cohort. We applied stepwise forward selection using expression data of 41 16q24.3 genes. The resulting optimal Cox-proportional hazards regression model included the genes APRT, CENPBD1, CHMP1A, and GALNS. Afterward, the prognostic value of the classifier was confirmed in an independent cohort of HNSCC patients treated by adjuvant radio(chemo)therapy (LMU-KKG cohort). The signature significantly differentiated high- and low-risk patients with regard to overall survival (HR = 2.01, 95% CI 1.10–3.70; P = 0.02125), recurrence-free survival (HR = 1.84, 95% CI 1.01–3.34; P = 0.04206), and locoregional recurrence-free survival (HR = 1.87, 95% CI 1.03–3.40; P = 0.03641). The functional impact of the four signature genes was investigated after reconstruction of a gene association network from transcriptome data of the TCGA HNSCC cohort using a partial correlation approach. Subsequent pathway enrichment analysis of the network neighborhood (first and second) of the signature genes suggests involvement of HNSCC-associated signaling pathways such as apoptosis, cell cycle, cell adhesion, EGFR, JAK-STAT, and mTOR. Furthermore, a detailed analysis of the first neighborhood revealed a cluster of co-expressed genes located on chromosome 16q, substantiating the impact of 16q24.3 alterations in poor clinical outcome of HNSCC. The reported gene expression signature represents a prognostic marker in HNSCC patients following postoperative radio(chemo)therapy.
AU  - Wintergerst, L.
AU  - Selmansberger, M.
AU  - Maihoefer, C.
AU  - Schüttrumpf, L.
AU  - Walch, A.K.
AU  - Wilke, C.
AU  - Pitea, A.
AU  - Woischke, C.*
AU  - Baumeister, P.
AU  - Kirchner, T.*
AU  - Belka, C.
AU  - Ganswindt, U.
AU  - Zitzelsberger, H.
AU  - Unger, K.
AU  - Hess J.
C1  - 54425
C2  - 45557
TI  - A prognostic mRNA expression signature of four 16q24.3 genes in radio(chemo)therapy-treated head and neck squamous cell carcinoma (HNSCC).
JO  - Mol. Oncol.
PY  - 2018
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by EWS-ETS translocations and early metastasis to lung and bone. In this study, we investigated the role of the BRICHOS chaperone domain-containing endochondral bone protein chondromodulin I (CHM1) in ES pathogenesis. CHM1 is significantly over-expressed in ES, and chromosome immunoprecipitation (ChIP) data demonstrate CHM1 to be directly bound by an EWS-ETS translocation, EWS-FLI1. Using RNA interference we observed that CHM1 promoted chondrogenic differentiation capacity of ES cells but decreased the expression of osteolytic genes such as HIF1A, IL6, JAG1 and VEGF. This was in line with the induction of the number of tartrate-resistant acid phosphatase (TRAP(+) ) stained osteoclasts in an orthotopic model of local tumor growth after CHM1 knock down, indicating that CHM1-mediated inhibition of osteomimicry might play a role in homing, colonization and invasion into bone tissues. We further demonstrate that CHM1 enhanced the invasive potential of ES cells in vitro. This invasiveness was in part mediated via CHM1-regulated MMP9 expression and correlated with the observation that, in an xenograft mouse model, CHM1 was essential for the establishment of lung metastases. This finding is in line with the observed increase in CHM1 expression in patient specimens with ES lung metastases. Our results suggest that CHM1 seems to have pleiotropic functions in ES, that need to be further investigated, but appears to be essential for the invasive and metastatic capacities of ES.
AU  - von Heyking, K.*
AU  - Calzada-Wack, J.
AU  - Göllner, S.*
AU  - Neff, F.
AU  - Schmidt, O.*
AU  - Hensel, T.*
AU  - Schirmer, D.*
AU  - Fasan, A.*
AU  - Esposito, I.*
AU  - Müller-Tidow, C.*
AU  - Sorensen, P.H.B.*
AU  - Burdach, S.*
AU  - Richter, G.H.*
C1  - 50750
C2  - 42516
CY  - Hoboken
SP  - 1288-1301
TI  - The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma.
JO  - Mol. Oncol.
VL  - 11
IS  - 9
PB  - Wiley
PY  - 2017
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - The human epidermal growth factor receptor 2 (HER2) and the protein tyrosine kinase 6 (PTK6) are often co- and over-expressed in invasive breast cancers. At early diagnosis, only distinct groups, such as HER2-or hormone receptor-positive benefit from a targeted therapy. However, a part of these tumours develops resistance within a year of administration of the drug but the majority of the patients depends on general therapies with severe side effects. A PTK6-directed approach does not yet exist. In our present study, we successfully demonstrate, in vitro and in vivo, a significantly additive reduction of tumourigenesis of breast cancer cells simultaneously depleted of both HER2 and PTK6. In comparison with single RNAi approaches, the combined RNAi (co-RNAi) led to a stronger reduced phosphorylation of tumour-promoting proteins. Moreover, the co-RNAi additively decreased cell migration as well as two and three dimensional cell proliferation in vitro. The in vivo experiments showed an additive reduction (p < 0.00001) in the growth of xenografts due to the co-RNAi compared with HER2 or PTK6 RNAi alone. Interestingly, the complexes of HER2 or PTK6 with tumour-relevant interaction partners, such as HER3 or the insulin-like growth factor receptor 1 (IGF-1R), respectively, were also reduced in xenografts although their protein expression levels were not affected following the co-RNAi of HER2 and PTK6. Our present study reveals the potential of using combined HER2- and PTK6- knockdown as a powerful strategy for the treatment of breast cancers. Therefore, the combined inhibition of these proteins may represent an attractive tool for efficient therapy of breast cancers.
AU  - Falkenberg, N.
AU  - Anastasov, N.
AU  - Höfig, I.
AU  - Bashkueva, K.
AU  - Lindner, K.
AU  - Höfler, H.
AU  - Rosemann, M.
AU  - Aubele, M.
C1  - 32344
C2  - 35007
CY  - Oxford
SP  - 282-294
TI  - Additive impact of HER2-/PTK6-RNAi on interactions with HER3 or IGF-1R leads to reduced breast cancer progression in vivo.
JO  - Mol. Oncol.
VL  - 9
IS  - 1
PB  - Elsevier Sci Ltd
PY  - 2015
SN  - 1574-7891
ER  - 

TY  - JOUR
AB  - The CATS protein was recently identified as a novel CALM interacting protein. CATS increases the nuclear and specifically the nucleolar localization of the leukemogenic CALM/AF10 fusion protein. We cloned and characterized the murine Cats gene. Detailed analysis of murine Cats expression during mouse embryogenesis showed an association with rapidly proliferating tissues. Interestingly, the Cats transcript is highly expressed in murine hematopoietic cells transformed by CALM/AF10. The CATS protein is highly expressed in leukemia, lymphoma and tumor cell lines but not in non-proliferating T-cells or human peripheral blood lymphocytes. CATS protein levels are cell cycle dependent and it is induced by mitogens, suggesting a role of CATS in the control of cell proliferation and possibly CALM/AF10-mediated leukemogenesis.
AU  - Fröhlich Archangelo, L.
AU  - Greif, P.A.
AU  - Hölzel, M.
AU  - Harasim, T.
AU  - Kremmer, E.
AU  - Przemeck, G.K.H.
AU  - Eick, D.
AU  - Deshpande, A.J.
AU  - Buske, C.
AU  - Hrabě de Angelis, M.
AU  - Saad, S.T.O.
AU  - Bohlander, S.K.
C1  - 3290
C2  - 25745
SP  - 356-367
TI  - The CALM and CALM/AF10 interactor CATS is a marker for proliferation.
JO  - Mol. Oncol.
VL  - 2
IS  - 4
PB  - Elsevier
PY  - 2008
SN  - 1574-7891
ER  -