BRAF inhibitors reprogram cancer-associated fibroblasts to drive matrix remodeling and therapeutic escape in melanoma
The tumor stroma and its cellular components are known to play an important role in tumor resilience towards treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitors (BRAFi)-induced non-canonical nuclear {beta}-catenin signaling in cancer-associated fibroblasts (CAFs). Our study reveals that BRAFi leads to an expanded CAF population with increased {beta}-catenin nuclear accumulation and enhances their biological properties. This CAF subpopulation is essential for melanoma cells to grow and resist to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF and CRAF dimerization and subsequently the activation of ERK signaling in CAFs, leading to the inactivation of the {beta}-catenin destruction complex. By RNA-Seq, periostin (POSTN) is identified as a major downstream effector of {beta} catenin in CAFs and can compensate for the loss of {beta}-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. Moreover, POSTN reactivates the ERK pathway, which is inhibited by BRAFi/MEKi, in melanoma cells through PI3K/AKT signaling. Our data underscore the roles of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma.