BRAF Inhibitors Reprogram Cancer-Associated Fibroblasts to Drive Matrix Remodeling and Therapeutic Escape in Melanoma

Abstract

The tumor stroma and its cellular components are known to play an important role in tumor response to treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitor (BRAFi)–induced noncanonical activation of nuclear β-catenin signaling in cancer-associated fibroblasts (CAF). Treatment with BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhanced biological properties. This CAF subpopulation is essential for melanoma cells to proliferate and acquire resistance to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF-CRAF heterodimerization and subsequent activation of ERK signaling in CAFs, leading to inactivation of the β-catenin destruction complex. RNA-seq identified periostin (POSTN) as a major downstream effector of β-catenin in CAFs. POSTN compensates for the loss of β-catenin in CAFs and mediates melanoma cell BRAFi/MEKi resistance. In melanoma cells, POSTN activates phosphoinositide 3-kinase (PI3K)/AKT signaling and subsequently reactivates the ERK pathway that was inhibited by BRAFi/MEKi. Collectively, these data underscore the role of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells. Significance: β-Catenin activation in cancer-associated fibroblasts in response to BRAF inhibitors stimulates POSTN secretion to promote resistance in cancer cells, revealing POSTN as a potential matrix target in cancer therapy.

Periostin secreted from podoplanin‐positive cancer‐associated fibroblasts promotes metastasis of gastric cancer by regulating cancer stem cells via AKT and YAP signaling pathway

“…To uncover the underlying mechanism behind the effects of PDPN(+) CAFs in promoting cell migration, we analyzed the differentially upregulated genes in mCAFs compared with nonCAFs using transcriptome data (Figure 3A). Among the top five genes, POSTN has been previously reported to be closely related to CAFs 17–19 . The upregulation of POSTN expression in PDPN(+) CAFs compared to PDPN(‐) CAFs and NFs was further validated by immunofluorescent staining (Figure 3B).…”

“…Previous studies have demonstrated that POSTN activates FAK and AKT pathways in cancer cells during tumor development 19,20 . Thus, we aimed to determine which pathways were activated by POSTN secreted from PDPN(+) CAFs.…”

Stromal Factors as a Target for Immunotherapy in Melanoma and Non-Melanoma Skin Cancers

“…Indeed, CD90+ fibroblast and FAP+ fibroblast counts are significantly positively associated with progression-free survival (PFS) and overall survival (OS), whereas a-SMA+ fibroblast count is negatively associated with PFS and OS in melanoma patients treated with anti-PD1 Abs monotherapy [ 100 ]. CAFs induce resistance not only in immunotherapy but also to BRAF inhibitors in advanced melanoma [ 101 , 102 ]. Indeed, BRAF inhibitors enhance β-catenin nuclear accumulation through the induction of BRAF-CRAF heterodimerization and subsequent activation of ERK signaling in both CAFs and melanoma cells, leading to proliferation of melanoma cells [ 101 ].…”

“…CAFs induce resistance not only in immunotherapy but also to BRAF inhibitors in advanced melanoma [ 101 , 102 ]. Indeed, BRAF inhibitors enhance β-catenin nuclear accumulation through the induction of BRAF-CRAF heterodimerization and subsequent activation of ERK signaling in both CAFs and melanoma cells, leading to proliferation of melanoma cells [ 101 ]. Berestjuk et al reported that extracellular matrix (ECM) derived from CAFs abrogate the anti-melanoma effects of BRAF/MEK inhibition in melanoma through discoidin domain receptors (DDR)1 and DDR2 phosphorylation [ 102 ].…”

The Role of Extracellular Matrix Remodeling in Skin Tumor Progression and Therapeutic Resistance

“…Moreover, BRAF inhibitors activate ERK signaling in CAFs, leading to activation of beta-catenin and the secretion of POSTN. This protein, in turn, reactivates ERK signaling in melanoma cells under BRAFi pressure, further promoting resistance ( Liu et al, 2022 ).…”