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  • 1
    Keywords: GENE ; TUMOR PROGRESSION ; B-RAF ; ACQUIRED-RESISTANCE ; COLORECTAL-CANCER CELLS ; senescence ; SELF-RENEWAL ; WNT/BETA-CATENIN ; HUMAN COLON ; SERRATED PATHWAY
    Abstract: Colon cancer cells frequently carry mutations that activate the beta-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/beta-catenin signals encourage ISC identity, we asked whether beta-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3beta. Similarly, transgenic expression of stabilized beta-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAFV637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/beta-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/beta-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.Oncogene advance online publication, 11 August 2014; doi:10.1038/onc.2014.247.
    Type of Publication: Journal article published
    PubMed ID: 25109331
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  • 2
    Keywords: TUMOR PROGRESSION ; SIGNALING PATHWAY ; COLON-CANCER ; K-RAS ; B-RAF ; ACQUIRED-RESISTANCE ; ISLAND METHYLATOR PHENOTYPE ; INTESTINAL STEM-CELLS ; MOLECULAR-FEATURES ; RAS GENE-MUTATIONS
    Abstract: Colorectal cancer (CRC) is characterized by recurrent mutations deregulating key cell signaling cascades and providing the cancer cells with novel functional traits. Among the most frequent mutations in CRC are gain-of-function missense mutations in KRAS and BRAF. Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs, respectively. Here we summarize genetic alterations currently described in the literature and databases, indicating overlapping but also specific co-occurrences with either mutated BRAF or KRAS. We describe common and potentially specific biological functions of KRAS and BRAF oncoproteins in the intestinal epithelial cells and during initiation and progression of CRC. We discuss signal transduction networks, highlighting individual functions of oncogenic KRAS and BRAF in terms of feedback loops and their impact on treatment outcome. Finally, we give an update on current strategies of targeted therapeutic intervention in oncogenic RAS-RAF signaling networks for the treatment of metastatic CRC and outline future directions.
    Type of Publication: Journal article published
    PubMed ID: 26299805
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