TY  - JOUR
AB  - MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein-coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs. IMPLICATIONS: This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.
AU  - Lee, J.L.*
AU  - Ekambaram, P.*
AU  - Carleton, N.M.*
AU  - Hu, D.*
AU  - Klei, L.R.*
AU  - Cai, Z.*
AU  - Myers, M.I.*
AU  - Hubel, N.E.*
AU  - Covic, L.*
AU  - Agnihotri, S.*
AU  - Krappmann, D.
AU  - Bornancin, F.*
AU  - Lee, A.V.*
AU  - Oesterreich, S.*
AU  - McAllister-Lucas, L.M.*
AU  - Lucas, P.C.*
C1  - 64125
C2  - 51670
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 373-386
TI  - MALT1 is a targetable driver of epithelial-to-mesenchymal transition in claudin-low, triple-negative breast cancer.
JO  - Mol. Cancer Res.
VL  - 20
IS  - 3
PB  - Amer Assoc Cancer Research
PY  - 2022
SN  - 1541-7786
ER  - 

TY  - JOUR
AB  - Murine liver tumors often fail to recapitulate the complexity of human hepatocellular carcinoma (HCC), which might explain the difficulty to translate preclinical mouse studies into clinical science. The aim of this study was to evaluate a subtyping approach for murine liver cancer models with regard to etiology-defined categories of human HCC, comparing genomic changes, histomorphology, and IHC profiles. Sequencing and analysis of gene copy-number changes [by comparative genomic hybridization (CGH)] in comparison with etiology-dependent subsets of HCC patients of The Cancer Genome Atlas (TCGA) database were conducted using specimens (75 tumors) of five different HCC mouse models: diethylnitrosamine (DEN) treated wild-type C57BL/6 mice, c-Myc and AlbLTαβ transgenic mice as well as TAK1LPC-KO and Mcl-1Δhep mice. Digital microscopy was used for the assessment of morphology and IHC of liver cell markers (A6-CK7/19, glutamine synthetase) in mouse and n = 61 human liver tumors. Tumor CGH profiles of DEN-treated mice and c-Myc transgenic mice matched alcohol-induced HCC, including morphologic findings (abundant inclusion bodies, fatty change) in the DEN model. Tumors from AlbLTαβ transgenic mice and TAK1LPC-KO models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLTαβ murine livers. CGH profiles from the Mcl-1Δhep model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity). IMPLICATIONS: Our findings demonstrate that stratifying preclinical mouse models along etiology-oriented genotypes and human-like phenotypes is feasible. This closer resemblance of preclinical models is expected to better recapitulate HCC subgroups and thus increase their informative value.
AU  - Friemel, J.*
AU  - Frick, L.*
AU  - Unger, K.
AU  - Egger, M.*
AU  - Parrotta, R.*
AU  - Boege, Y.T.*
AU  - Adili, A.*
AU  - Karin, M.*
AU  - Luedde, T.*
AU  - Heikenwalder, M.*
AU  - Weber, A.*
C1  - 55836
C2  - 46602
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 1493-1502
TI  - Characterization of HCC mouse models: Towards an etiology-oriented subtyping approach.
JO  - Mol. Cancer Res.
VL  - 17
IS  - 7
PB  - Amer Assoc Cancer Research
PY  - 2019
SN  - 1541-7786
ER  - 

TY  - JOUR
AB  - Increased levels of the chemokine CCL2 in cancer patients are associated with poor prognosis. Experimental evidence suggests that CCL2 correlates with inflammatory monocyte recruitment and induction of vascular activation, but the functionality remains open. Here, we show that endothelial Ccr2 facilitates pulmonary metastasis using an endothelial-specific Ccr2-deficient mouse model (Ccr2 ec KO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2 ec KO and Ccr2 fl / fl littermates were observed. The absence of endothelial Ccr2 strongly reduced pulmonary metastasis, while the primary tumor growth was unaffected. Despite a comparable cytokine milieu in Ccr2 ec KO and Ccr2 fl / fl littermates the absence of vascular permeability induction was observed only in Ccr2 ec KO mice. CCL2 stimulation of pulmonary endothelial cells resulted in increased phosphorylation of MLC2, endothelial cell retraction, and vascular leakiness that was blocked by an addition of a CCR2 inhibitor. These data demonstrate that endothelial CCR2 expression is required for tumor cell extravasation and pulmonary metastasis. Implications: The findings provide mechanistic insight into how CCL2–CCR2 signaling in endothelial cells promotes their activation through myosin light chain phosphorylation, resulting in endothelial retraction and enhanced tumor cell migration and metastasis.
AU  - Roblek, M.*
AU  - Protsyuk, D.*
AU  - Becker, P.F.
AU  - Stefanescu, C.*
AU  - Gorzelanny, C.*
AU  - Garzon, J.F.G.*
AU  - Knopfova, L.*
AU  - Heikenwälder, M.
AU  - Luckow, B.*
AU  - Schneider, S.W.*
AU  - Borsig, L.*
C1  - 55667
C2  - 46445
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 783-793
TI  - CCL2 is a vascular permeability factor inducing CCR2-dependent endothelial retraction during lung metastasis.
JO  - Mol. Cancer Res.
VL  - 17
IS  - 3
PB  - Amer Assoc Cancer Research
PY  - 2019
SN  - 1541-7786
ER  - 

TY  - JOUR
AB  - Despite effective strategies, resistance in HER2(+) breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2(+) models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2(+) breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation.
AU  - Sethunath, V.*
AU  - Hu, H.*
AU  - de Angelis, C.*
AU  - Veeraraghavan, J.*
AU  - Qin, L.*
AU  - Wang, N.*
AU  - Simon, L.
AU  - Wang, T.*
AU  - Fu, X.*
AU  - Nardone, A.*
AU  - Pereira, R.*
AU  - Nanda, S.*
AU  - Griffith, O.L.*
AU  - Tsimelzon, A.*
AU  - Shaw, C.*
AU  - Chamness, G.C.*
AU  - Reis-Filho, J.S.*
AU  - Weigelt, B.*
AU  - Heiser, L.M.*
AU  - Hilsenbeck, S.G.*
AU  - Huang, S.*
AU  - Rimawi, M.F.*
AU  - Gray, J.W.*
AU  - Osborne, C.K.*
AU  - Schiff, R.*
C1  - 57378
C2  - 47715
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 2318-2330
TI  - Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer.
JO  - Mol. Cancer Res.
VL  - 17
IS  - 11
PB  - Amer Assoc Cancer Research
PY  - 2019
SN  - 1541-7786
ER  - 

TY  - JOUR
AB  - Most lung cancer deaths are related to metastases, which indicates the necessity of detecting and inhibiting tumor cell dissemination. Here, we aimed to identify miRNAs involved in metastasis of lung adenocarcinoma as prognostic biomarkers and therapeutic targets. To that end, lymph node metastasis- associated miRNAs were identified in The Cancer Genome Atlas lung adenocarcinoma patient cohort (sequencing data; n = 449) and subsequently validated by qRT-PCR in an independent clinical cohort (n = 108). Overexpression of miRNAs located on chromosome 14q32 was associated with metastasis in lung adenocarcinoma patients. Importantly, Kaplan-Meier analysis and log-rank test revealed that higher expression levels of individual 14q32 miRNAs (mir-539, mir-323b, and mir- 487a) associated with worse disease-free survival of never-smoker patients. Epigenetic analysis including DNA methylation microarray data and bisulfite sequencing validation demonstrated that the induction of 14q32 cluster correlated with genomic hypomethylation of the 14q32 locus. CRISPR activation technology, applied for the first time to functionally study the increase of clustered miRNA levels in a coordinated manner, showed that simultaneous overexpression of 14q32 miRNAs promoted tumor cell migratory and invasive properties. Analysis of individual miRNAs by mimic transfection further illustrated that miR-323b-3p, miR-487a-3p, and miR-539-5p significantly contributed to the invasive phenotype through the indirect regulation of different target genes. In conclusion, overexpression of 14q32 miRNAs, associated with the respective genomic hypomethylation, promotes metastasis and correlates with poor patient prognosis in lung adenocarcinoma. Implications: This study points to chromosome 14q32miRNAs as promising targets to inhibit tumor cell dissemination and to predict patient prognosis in lung adenocarcinoma. Mol Cancer Res; 16(3); 390-402.
AU  - Gonzalez-Vallinas, M.*
AU  - Rodriguez-Paredes, M.*
AU  - Albrecht, M.*
AU  - Sticht, C.*
AU  - Stichel, D.*
AU  - Gutekunst, J.*
AU  - Pitea, A.
AU  - Sass, S.
AU  - Sánchez-Rivera, F.J.*
AU  - Bermejo, J.L.*
AU  - Schmitt, J.*
AU  - De La Torre, C.*
AU  - Warth, A.*
AU  - Theis, F.J.
AU  - Müller, N.S.
AU  - Gretz, N.*
AU  - Muley, T.*
AU  - Meister, M.*
AU  - Tschaharganeh, D.F.*
AU  - Schirmacher, P.*
AU  - Matthäus, F.*
AU  - Breuhahn, K.*
C1  - 52726
C2  - 44242
CY  - Philadelphia
SP  - 390-402
TI  - Epigenetically regulated chromosome 14q32 miRNA cluster induces metastasis and predicts poor prognosis in lung adenocarcinoma patients.
JO  - Mol. Cancer Res.
VL  - 16
IS  - 3
PB  - Amer Assoc Cancer Research
PY  - 2018
SN  - 1541-7786
ER  - 

TY  - JOUR
AB  - Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of human epidermal growth factor receptor 2 (HER2) and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately 30 % of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. Additionally, dual knockdown stronger reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27 and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer.
AU  - Ludyga, N.
AU  - Anastasov, N.
AU  - Rosemann, M.
AU  - Seiler, J.
AU  - Lohmann, N.
AU  - Braselmann, H.
AU  - Mengele, K.*
AU  - Schmitt, M.*
AU  - Höfler, H.
AU  - Aubele, M.
C1  - 23129
C2  - 31003
SP  - 381-392
TI  - Effects of simultaneous knockdown of HER2 and PTK6 on malignancy and tumor progression in human breast cancer cells.
JO  - Mol. Cancer Res.
VL  - 11
IS  - 4
PB  - Amer. Assoc. Cancer Research
PY  - 2013
SN  - 1541-7786
ER  - 

TY  - JOUR
AB  - Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1.
AU  - Grunewald, T.G.*
AU  - Diebold, I.*
AU  - Esposito, I.
AU  - Plehm, S.*
AU  - Hauer, K.*
AU  - Thiel, U.*
AU  - Da Silva-Buttkus, P.
AU  - Neff, F.
AU  - Unland, R.*
AU  - Müller-Tidow, C.*
AU  - Zobywalski, C.*
AU  - Lohrig, K.*
AU  - Lewandrowski, U.*
AU  - Sickmann, A.*
AU  - da Costa, O.P.*
AU  - Görlach, A.*
AU  - Cossarizza, A.*
AU  - Butt, E.*
AU  - Richter, G.H.*
AU  - Burdach, S.*
C1  - 7177
C2  - 29522
SP  - 52-65
TI  - STEAP1 is associated with the invasive and oxidative stress phenotype of Ewing tumors.
JO  - Mol. Cancer Res.
VL  - 10
IS  - 1
PB  - Amer Assoc Cancer Research
PY  - 2012
SN  - 1541-7786
ER  - 

TY  - JOUR
AB  - Prostate carcinoma (CaP) is a leading cause of cancer-related death in men. We have previously determined the microRNA (miRNA) profile of primary CaP in comparison with nontumor prostate tissue. miRNAs are small, noncoding RNAs that inhibit protein synthesis on a posttranscriptional level by binding to the 3'-untranslated region (3'-UTR) of their target genes. In primary CaP tissue, we have previously found by miRNA sequencing that miR-375 and miR-200c were upregulated 9.1- and 4.5-fold, respectively. A computational analysis predicted the 3'-UTR of the SEC23A gene as a potential target for both miR-375 and miR-200c. Here, we show that the 3'-UTR of SEC23A mRNA is indeed a target for miR-375 and miR-200c and that both miRNAs downregulate Sec23A protein expression when ectopically expressed in human 293T cells. In primary samples of CaP, we found a direct correlation between reduction of SEC23A mRNA and overexpression of miR-375 but not of miR-200c. The reduced levels of Sec23A protein were inversely correlated to the increased amount of miR-375 in the LNCaP and DU145 CaP cell lines when compared with normal prostate fibroblasts. In primary CaP, we also detected decreased amounts of Sec23A protein when compared with corresponding normal prostate tissue. Ectopically overexpressed Sec23A in LNCaP and DU145 CaP cells significantly reduced the growth properties, indicating that Sec23A might play a role in the induction or growth of prostate carcinoma. Sec23A overexpression reduced cell growth but did not induce apoptosis, whereas inhibition of Sec23A stimulated cell proliferation.
AU  - Szczyrba, J.*
AU  - Nolte, E.*
AU  - Wach, S.*
AU  - Kremmer, E.
AU  - Stöhr, R.*
AU  - Hartmann, A.*
AU  - Wieland, W.*
AU  - Wullich, B.*
AU  - Grässer, F.A.*
C1  - 6238
C2  - 28653
SP  - 791-800
TI  - Downregulation of Sec23A protein by miRNA-375 in prostate carcinoma.
JO  - Mol. Cancer Res.
VL  - 9
IS  - 6
PB  - Amer Assoc Cancer Research
PY  - 2011
SN  - 1541-7786
ER  -