4.8 Article

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

Journal

CELL REPORTS
Volume 21, Issue 13, Pages 3833-3845

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2017.11.104

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Funding

  1. NCI [R01CA190558]
  2. Human Genetics Institute of New Jersey
  3. New Jersey Commission on Cancer Research [DHFS16PPC036, DHSFS17PPC020, DFHS13PPC034]
  4. Summer Undergraduate Research Fellowship
  5. Aresty Research Center for Undergraduates
  6. NIDDK
  7. NIAID [U01DK103141]
  8. Initiative for Multidisciplinary Research Teams award from Rutgers University, Newark, NJ
  9. [P30CA072720]

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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 findings help resolve the conditions necessary for BRAF-driven colon cancer initiation. Additionally, our results predict that genetic and/or environmental factors that reduce tissue differentiation will increase susceptibility to serrated colon cancer. These findings offer an opportunity to identify susceptible individuals by assessing their tissue-differentiation status.

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