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

• DOI: 10.1016/j.celrep.2017.11.104
• Publication Date: 2017-12-26T11:42:29Z
• Authors: Kevin Tong; Oscar Pellón-Cárd...; Veerin R. Sirihor...; Bailey N. Warder; Om A. Kothari; Ansu O. Perekatt; Emily E. Fokas; Robert L. Fullem; Anbo Zhou; Joshua K. Thackray; Hiep Tran; Lanjing Zhang; Jinchuan Xing; Michael P. Verzi
• Keywords: Degree (music)

Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer unclear. We find that oncogenic paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient mouse models cancer. By reducing levels differentiation via genetic manipulation either two distinct differentiation-promoting factors (Smad4 or Cdx2), activity restored BRAFV600E intestines, capacity amplified. In human patients, we observe reduced normal tissue associated with increased susceptibility tumors. Together, these findings help resolve conditions necessary for initiation. Additionally, our results predict and/or environmental reduce will increase These offer an opportunity identify susceptible individuals by assessing their tissue-differentiation status.