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ERK1/2 controlled genes ANGPT2 and CXCR4 mediate liver metastasis from colon cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142219 | GEO | 2020/07/31

REPOSITORIES: GEO

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Project description:Background: Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC) and is a major health burden. Most molecular studies of CRC have profiled primary tumor samples and not the metastasis samples. In this study, we compared the copy number profiles of matched primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. This has important implications for whether it is justified to base therapeutic approaches solely on data from the primary tumour. Methods: Paired primary and metastatic tumours from 16 patients and their adjacent normal tissue samples were analyzed using Single-Nucleotide-Polymorphism (SNP) arrays to determine copy number alterations. Nine patients had a synchronous liver metastasis at the time of CRC diagnosis and 7 patients developed a liver metastasis metachronously. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 189 genes known to be somatically altered in CRC and 25 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. Results: The genomic divergence with the whole genome duplication correction applied the average percent copy number discordance across all pairs of samples was 22.02%. The pairs of tumour samples collected prior to treatment revealed a significantly higher copy number differences compared to previously treated liver metastasis samples (P=0.024). However, loss of heterozygosity (LOH) acquired in metastasis was significantly higher in previously treated liver metastasis samples compared to treatment naïve liver metastasis samples (P= 0.0064) and which included where KRAS mutation was present in the primary cancers but was not detectable in the metastatic sample following chemotherapy. With regard to 25 genes that are clinically actionable in CRC, amplification of the genes ERBB2, FGFR1, CDK8 or PIK3CA was observed in the metastatic tissue of 4 patients but not in the matched primary CRC. In these cases, knowledge of these metastatic specific alterations could have informed therapeutic decision making and may have improved patient outcome. Conclusion: Intra-patient genomic discrepancies observed between primary and metastatic tissue

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ERK1/2 controlled genes ANGPT2 and CXCR4 mediate liver metastasis from colon cancer

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