FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.

Abstract

BRAF ^V600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF^V600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a "just-right" level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAF^V600E-mutant adenomas/polyps in mice and patients. In Vill-Cre;BRAF^V600E/+;Fak^fl/fl mice, Fak deletion maximized BRAF^V600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAF^V600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a "just-right" ERK signaling optimal for BRAF^V600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.