Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer.

ABSTRACT: Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAF^V600E intestines, and the oncogenic capacity of BRAF^V600E is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these finding

SUBMITTER: Tong K 

PROVIDER: S-EPMC5747303 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature