M-Wnt claudin-low breast cancer model : metastatic derivatives
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98703 | GEO | 2017/05/10
SECONDARY ACCESSION(S): PRJNA385955
REPOSITORIES: GEO
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Project description:Colorectal cancer, a leading cause of cancer-related mortality due to distant metastases, is largely driven by activating mutations in the WNT and MAPK pathways. Understanding the mechanism underlying the various steps involved in the metastatic process is essential for developing effective treatments. Using serial in vivo orthotopic passaging, we developed an immunocompetent mouse model of metastatic colorectal cancer. We demonstrate that highly metastatic tumor cells exhibit chromosomal amplifications in MAPK pathway genes, leading to increased MAPK activity, which in turn suppresses WNT-associated transcriptional programs, including stem cell genes. Pharmacological inhibition of mutant KRASG12D led to a reduction in the MAPK-high/ WNT-low transcriptional state and effectively decreased metastatic dissemination both to the lung and liver. Analysis of CRC patient data revealed that the metastatic gene signature associated with the MAPK-high/ WNT-low state correlated with poorer survival outcomes. These findings underscore the plasticity of metastasis-initiating cells in CRC that arise due to the opposing roles of MAPK and WNT signaling, despite the apparent synergy of these pathways observed during colon tumorigenesis.
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