ERK1/2 controlled genes ANGPT2 and CXCR4 mediate liver metastasis from colon cancer
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ABSTRACT:
PROVIDER: PRJNA596235 | ENA |
REPOSITORIES: ENA
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Project description:Carcinoma development in colorectal cancer (CRC) is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of CRC metastatic disease, but how RAS-ERK signaling regulates CRC metastasis is still unknown. An unbiased screening approach based on selection of highly liver metastatic CRC cells in vivo was used to determine genes associated with metastasis and a ERK1/2-controlled metastatic gene set (EMGS) defined. The ANGPT2 and CXCR4, two genes within the gene set, were subjected to gain and loss of function validation in CRC cells (SW620, SW480, Colo26, HCT116), its downstream mechanism validated, and tested in clinical samples. Here, we identified an EMGS that is associated with increased recurrence and reduced survival for patients with CRC tumors. Higher levels of EMGS expression were detected in the CRC subsets Consensus Molecular Subtype (CMS)1 and CMS4. We show that the RAS-ERK1/2 axis controls the expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in CRC cells, and that this facilitates the development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are essential for metastatic outgrowth in the liver. We also show that CXCR4 also controls the expression of the cytokines IL10 and CXCL1, and provide evidence for a causal role of IL10 in supporting liver colonization. In summary, we demonstrate that amplification of ERK1/2 signaling in KRAS-mutated CRC cells affects the cytokine milieu of the tumors, thus possibly affecting tumor?stroma interactions and favoring liver metastasis formation.
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Project description:Glomerular diseases are the leading cause of chronic kidney diseases with pathomechanisms largely unclear. It is known that ANGPT2 regulates endothelial cell homeostasis and function via TEK/TIE2 and its deregulation causes endothelial damage. We found that ANGPT2 is upregulated in glomerular diseases and wondered whether it has any effect on glomerular podocytes and mesangial cells given that they have no or low TEK expression. We treated podocytes and mesangial cells in culture with ANGPT2 and found no overt cellular changes. RNA-seq analysis showed that gene expression was altered in both podocytes and mesangial cells and that the regulated genes in the two cell types were fundamentally different. GO and KEGG analyses showed that the two groups of regulated genes were enriched in distinct processes and pathways. These results suggest that ANGPT2 exerts effects on both podocytes and mesangial cells and that increased ANGPT2 may be involved in glomerular injury by affecting podocytes and mesangial cells in addition to endothelial cells.
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