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Cell Rep. 2017 Dec 26;21(13):3833-3845. doi: 10.1016/j.celrep.2017.11.104.

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

Author information

1
Department of Genetics, Rutgers University, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA; Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA.
2
Department of Genetics, Rutgers University, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA.
3
Waksman Institute, Rutgers University, Piscataway, NJ 08854, USA.
4
Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pathology, University Medical Center of Princeton, Plainsboro, NJ 08536, USA.
5
Department of Genetics, Rutgers University, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA; Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA. Electronic address: verzi@biology.rutgers.edu.

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 BRAFV600E intestines, and the oncogenic capacity of BRAFV600E 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.

KEYWORDS:

BRAF; Cdx2; Smad4; intestinal homeostasis; serrated colorectal cancer

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