Gene expression after knocking down of c-Met in breast cancer brain metastatic cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74968 | GEO | 2016/03/01
SECONDARY ACCESSION(S): PRJNA302058
REPOSITORIES: GEO
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Project description:The purpose of this study is to identify the target genes of c-Met signaling in breast cancer brain metastasis. 231BrM/Dox/shMet and SKBrM3/Dox/shMet cells were treated with or without doxycycline for 48hrs.
2016-03-01 | E-GEOD-74968 | biostudies-arrayexpress
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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.
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Project description:MET exon 14 skipping alteration (MET∆14Ex) is an actionable oncogenic driver that occurs in 2-4% of non-small cell lung cancer (NSCLC) cases. However, the precise role of MET∆14Ex in tumor progression in NSCLC is poorly understood. We here demonstrate that MET∆14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, which significantly boosts tumor cell scattering and invasion as well as metastasis. To explore the key mechanisms in regulation of these phenotypes, RNA sequencing (RNA-seq) studies were conducted on HGF-treated MET∆14Ex and MET cell models in an effort to identify the global change of transcriptome signature and key functional pathways involved in MET∆14Ex-medieated tumorigenesis. Both Ingenuity pathway analysis (IPA) and gene set enrichment analysis (GSEA) revealed an induction of a tight cluster of functional pathways associated with cell movement in HGF-treated MET∆14Ex models (vs MET) in a time-dependent manner.
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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.
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Project description:We studied MET-transformed human primary osteoblasts (MET-HOBs), which we previously turned into osteosarcoma cells by LV driven over-expression of MET oncogene. We obtained distinct MET transformed HOB clones derived from independent events of transgene integration. To characterise the phenotype of the MET-HOB clones we used oligonucleotide microarrays. Expression profiles of MET-HOBs and osteosarcoma cell lines were compared.
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Project description:This experiment investigates In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. The goal of this study was to examine the effects of AMG337 on proliferation in cancer cell lines with varying MET copy number, the hypothesis being that high-level focal MET amplification is required to confer MET oncogene addiction and AMG337 sensitivity.
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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
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Project description:We studied MET-transformed human primary osteoblasts (MET-HOBs), which we previously turned into osteosarcoma cells by LV driven over-expression of MET oncogene. We obtained distinct MET transformed HOB clones derived from independent events of transgene integration. To characterise the phenotype of the MET-HOB clones we used oligonucleotide microarrays. Expression profiles of MET-HOBs and osteosarcoma cell lines were compared. To characterise the phenotype of the MET-HOB clones we used oligonucleotide microarrays
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