FAK loss reduces BRAF^V600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation

Area of Science:

• Oncology
• Molecular Biology
• Gastroenterology

Background:

• The BRAF^V600E mutation drives colorectal cancer via the serrated pathway, leading to constitutive extracellular signal-regulated kinase (ERK) activation.
• While high ERK activation can suppress tumors, the optimal level for tumorigenesis is unknown.
• Focal adhesion kinase (FAK) expression is reduced in BRAF^V600E-mutant colorectal tumors.

Approach:

• Investigated the role of FAK in BRAF^V600E-driven colorectal tumorigenesis using genetically engineered mouse models (Vill-Cre;BRAF^V600E/+;Fak^fl/fl).
• Assessed the impact of FAK deletion on ERK pathway activation, Lgr4 levels, and tumor incidence.
• Examined the mechanistic link between FAK loss, ERK phosphorylation, and intestinal stemness.

Key Points:

• FAK deletion in BRAF^V600E-mutant mice led to 100% cecal tumor incidence.
• FAK loss reduced epidermal growth factor receptor (EGFR)-dependent ERK phosphorylation without altering transcriptional output.
• Reduced ERK phosphorylation increased Lgr4 levels, enhancing intestinal stemness and promoting tumor formation.

Conclusions:

• FAK plays a critical role in regulating the oncogenic activity of BRAF^V600E.
• A precise level of ERK signaling, achieved through FAK-mediated downregulation of ERK phosphorylation, is optimal for BRAF^V600E-induced colorectal tumorigenesis.
• Targeting FAK could be a therapeutic strategy for BRAF^V600E-mutant colorectal cancers.