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

Abstract

Summary 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 which 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.

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells

“…With this caveat acknowledged, inhibition of MEK prior to Wnt inhibition blocked proliferation and differentiation of ISCs into TA cells and impaired intestinal homeostasis shortly after C59 administration. This model is consistent with studies showing that increased MAPK signaling in the intestine due to BRAFV600 mutation promotes loss of ISCs and increases differentiation (26,27).…”

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

“…Furthermore, explorative analyses within the chemo‐naïve stage I–III subgroup suggest that CDX2 carries prognostic information for cancers with BRAF mutations, within both the MSI and MSS subtypes separately, highlighting CDX2 as a potential biomarker with additional prognostic information to MSI and BRAF status. This finding is in line with recent studies reporting synergistic oncogenic activity between loss of CDX2 and BRAF mutation in serrated tumors (Sakamoto et al ., 2017; Tong et al ., 2017), which is associated with more aggressive disease and a poor prognosis (Garcia‐Solano et al ., 2010). …”

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

“…Such heterogeneity may result from secondary genetic mutations. In many cases, however, it cannot be linked to a clear genetic cause, but rather appears to be associated with epigenetic factors established by a cell's developmental lineage or differentiation state [2][3][4][5][6][7][8][9][10] . A paradigmatic example of epigenetic heterogeneity in the state of oncogene dependency is observed among melanomas that carry V600E/D/K mutations in the BRAF oncogene.…”