Clinical Implication of Concurrent Amplification of MET and FGFR2 in Metastatic Gastric Cancer
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ABSTRACT:
PROVIDER: PRJEB69296 | ENA |
REPOSITORIES: ENA
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| S-EPMC10740780 | biostudies-literature
Project description:We found that RANKL, expressed by cancer cells or derived from exogenous sources, consistently induced human prostate, breast, kidney, lung and liver cancer cells to colonize or metastasize to bone in an animal model of cancer bone metastasis. RANK-mediated signaling established a premetastatic niche through a forward feedback loop by inducing RANKL and c-Met expression and downstream signaling via upregulation of master regulator transcription factors regulating EMT (Twist1, Slug, Zeb1, Zeb2), stem cells (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine cells (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream signaling network, c-Myc/Max or c-Met, abolished PCa skeletal metastasis in mice. We observed that a small number of RANKL-expressing PCa cells can initiate bone and soft tissue metastases by recruiting non-tumorigenic or bystander PCa or host cells from the circulation or at metastatic sites to co-colonize bone. The recruited bystander PCa cells assume the phenotypes of RANKL-expressing PCa cells by expressing increased c-Met, phosphorylated c-Met and RANKL. RANKL expression at a single cell level in primary PCa tissues predicted disease-specific survival, reflecting the significant role of RANKL-RANK signaling in the development of lethal bone metastasis.
2014-02-06 | GSE48432 | GEO
Project description:We found that RANKL, expressed by cancer cells or derived from exogenous sources, consistently induced human prostate, breast, kidney, lung and liver cancer cells to colonize or metastasize to bone in an animal model of cancer bone metastasis. RANK-mediated signaling established a premetastatic niche through a forward feedback loop by inducing RANKL and c-Met expression and downstream signaling via upregulation of master regulator transcription factors regulating EMT (Twist1, Slug, Zeb1, Zeb2), stem cells (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine cells (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream signaling network, c-Myc/Max or c-Met, abolished PCa skeletal metastasis in mice. We observed that a small number of RANKL-expressing PCa cells can initiate bone and soft tissue metastases by recruiting non-tumorigenic or bystander PCa or host cells from the circulation or at metastatic sites to co-colonize bone. The recruited bystander PCa cells assume the phenotypes of RANKL-expressing PCa cells by expressing increased c-Met, phosphorylated c-Met and RANKL. RANKL expression at a single cell level in primary PCa tissues predicted disease-specific survival, reflecting the significant role of RANKL-RANK signaling in the development of lethal bone metastasis. Global gene expression analysis perturbed by RANKL in LNRANKL compared to LNNeo cells.
2014-02-06 | E-GEOD-48432 | biostudies-arrayexpress
Project description:Tumor-derived exosomes are emerging as mediators of tumorigenesis with a tissue-specific address and message. We explored the function of melanoma-derived exosomes in formation of primary tumors and metastatic progression in both murine models and patients. Whereas exosomes from highly metastatic melanoma cells increased the metastatic behavior of primary tumor cells by educating bone marrow (BM) progenitor cells via the MET receptor, exosomes from low metastatic melanoma cells did not alter the incidence of metastases. Melanoma-derived exosomes induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitor cells towards a pro-vasculogenic phenotype (c-Kit+Tie2+MET+). Reducing MET expression in tumor-derived exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was upregulated in circulating BM progenitor cells (CD45-CD117low and CD45-CD117lowTIE2+) isolated from stage III and stage IV melanoma patients. Rab1a, Rab5b, Rab7, and Rab27a were highly expressed in melanoma and Rab27a RNA interference decreased exosome production and/or soluble angiogenic factors in melanoma cells, thereby preventing mobilization of BM progenitor cells, tumor growth and metastasis. Finally, we identified a melanoma signature in exosomes isolated from metastatic melanoma patients, comprised of TYRP2, VLA-4, Hsp70, an Hsp90 isoform and MET oncoprotein, which together with Rab proteins, appear to represent exosome-specific proteins with prognostic potential, and may provide new therapeutic targets. Identification of molecular finger associated to exosome effects in metastatic organs Microarray analysis of genes differentially expressed in the lungs 24 and 48 hours after B16-F10 exosome tail vein injection compared to control.
2012-05-26 | E-GEOD-36584 | biostudies-arrayexpress
Project description:Tumor-derived exosomes are emerging as mediators of tumorigenesis with a tissue-specific address and message. We explored the function of melanoma-derived exosomes in formation of primary tumors and metastatic progression in both murine models and patients. Whereas exosomes from highly metastatic melanoma cells increased the metastatic behavior of primary tumor cells by educating bone marrow (BM) progenitor cells via the MET receptor, exosomes from low metastatic melanoma cells did not alter the incidence of metastases. Melanoma-derived exosomes induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitor cells towards a pro-vasculogenic phenotype (c-Kit+Tie2+MET+). Reducing MET expression in tumor-derived exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was upregulated in circulating BM progenitor cells (CD45-CD117low and CD45-CD117lowTIE2+) isolated from stage III and stage IV melanoma patients. Rab1a, Rab5b, Rab7, and Rab27a were highly expressed in melanoma and Rab27a RNA interference decreased exosome production and/or soluble angiogenic factors in melanoma cells, thereby preventing mobilization of BM progenitor cells, tumor growth and metastasis. Finally, we identified a melanoma signature in exosomes isolated from metastatic melanoma patients, comprised of TYRP2, VLA-4, Hsp70, an Hsp90 isoform and MET oncoprotein, which together with Rab proteins, appear to represent exosome-specific proteins with prognostic potential, and may provide new therapeutic targets. Identification of molecular finger associated to exosome effects in metastatic organs
2012-05-27 | GSE36584 | GEO
Project description:We used microarrays to probe the global programme of gene expression under treatment with c-Met inhibitor and identified distinct classes of up- and down-regulated genes during this process We treated MET addicted EBC-1 and MKN-45 cells with selective c-Met kinase inhibitor SGX-523 at 1uM for 24 and 48 hours, using HCC827 cells with activated c-Met but lacking MET dependency as a negative control
2015-02-12 | E-GEOD-65854 | biostudies-arrayexpress
Project description:Genome-wide association studies have identified a locus within the second intron of the FGFR2 gene that is consistently the most strongly associated with estrogen receptor-poisive breast cancer risk. However, we know little about the mechanisms by which the FGFR2 locus mediates risk or the pathways in which multiple risk loci may combine to cause disease. Previously, a systems biology approach was adopted to elucidate the regulatory networks operating in MCF-7 breast cancer cells in order to examine the role of FGFR2 in mediating risk. Here, the same approach has been employed using MCF-7 cells that have been treated with siRNA directed against FGFR2, in order to knock-down FGFR2 expression, to confirm that the differential gene expression that we see when FGF10 signalling is perturbed, on a background of estrogen signalling, is mediated via FGFR2 stimulation.
2016-02-01 | GSE74146 | GEO
Project description:MET amplification is present in 20% of gastric cancers and has been confirmed as a therapeutic target in clinical trials. The molecular mechanisms of response and resistance to MET inhibitors are not well understood. We investigated the determinants of MET dependency in human gastric cancer. MET inhibition inhibited proliferation and induced cell death only in MET-amplified gastric cancer cell lines. The effects on growth arrest were stronger than the effects on cell death. To identify possible resistance mechanisms, we performed whole-genome mRNA expression profiling. Molecular changes related to autophagy were among the top alterations observed. Consistent with these findings, autophagy levels increased in a concentration-dependent manner when MET-amplified cells were exposed to crizotinib. Autophagy inhibition caused a dramatic decrease in apoptosis in one of the MET-amplified cell lines (MKN45) but not in the other (SNU-5). Because autophagy may provide energy in cells subjected to growth factor deprivation, we explored the effects of MET or autophagy inhibition on cellular ATP levels. This revealed that autophagy-dependent ATP production was selectively required for apoptosis in the MKN45 cells and that chemical ATP depletion mimicked the effects of autophagy inhibition to block cell death. Overall, the data reveal a novel relationship between ATP depletion and resistance to MET inhibitor-induced cell death. Our observations suggest that autophagy inhibitors could have unintended consequences when they are combined with growth factor receptor inhibitors in tumors that require autophagy-dependent ATP production for apoptosis. 12 samples triplicate samples of SNU-5 and MKN45 +/- criztonib for 24 hours
2016-05-13 | E-GEOD-77320 | biostudies-arrayexpress
Project description:B16-F10 malignant mouse melanoma cells have been frequently used as highly metastatic cells. Based on heterogenous cell surface expression of Met/HGF (hepatocyte growth factor) receptor in B16-F10 cells, the cells were divided into Met-low and Met-high cells by flow cytometry and these populations were subjected to microarray analysis. Met-low and Met-high cells showed different expression profiles in genes involved characteristics of tumors, including stem cell maintenance, pigmentation, and angiogenesis.
2016-09-25 | GSE69741 | GEO
Project description:MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug-sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine, or RNAi-mediated knockdown of two obligate components of the autophagy pathway (ATG5 and ATG7) blocked cell death induced by crizotinib or RNAi-mediated knockdown of MET, and mechanistic studies localized the effects of autophagy to cytochrome c release from the mitochondria. Overall; the data reveal a novel relationship between autophagy and apoptosis in gastric cancer cells exposed to MET inhibitors. The observations suggest that autophagy inhibitors should not be used to enhance the effects of MET inhibitors in gastric cancer patients.
2016-05-13 | GSE77320 | GEO