POSTN驱动的机械转导维持CAFs中beta-catenin活性以促进黑色素瘤进展和耐药

Cancer-associated fibroblasts (CAFs) are pivotal modulators of the tumor microenvironment, orchestrating extracellular matrix (ECM) remodeling, inflammation, and therapeutic resistance. However, the mechanisms governing their dynamic response to targeted therapies, particularly in melanoma, remain incompletely understood. Our previous work identified beta-catenin as a central driver of CAF activation in melanoma. Building on this, we recently discovered that periostin (POSTN), a matricellular protein primarily secreted by CAFs, acts as a major downstream effector of beta-catenin-mediated transcriptional reprogramming.In this study, we uncover a novel beta-catenin-TCF-POSTN regulatory axis that underlies CAF-mediated resistance to BRAF inhibition in melanoma. Specifically, we show that nuclear beta-catenin interacts with TCF4 to drive POSTN expression and secretion in CAFs. Disrupting this interaction, using a dominant-negative TCF4 mutant or the pharmacological inhibitor PNU74654, significantly reduced POSTN expression, mimicking the effects of beta-catenin inhibition. Phenotypically, POSTN depletion impaired CAF proliferation, cytoskeletal dynamics, and their ability to promote melanoma cell proliferation and resistance to BRAF inhibition in vitro .Mechanistically, we identified a POSTN-driven outside-in mechanotransduction loop in which POSTN activates integrin-focal adhesion signaling to promote actin stress fiber assembly. The resulting cytoskeletal tension induced nuclear deformation, facilitating beta-catenin nuclear translocation, thereby sustaining POSTN expression and reinforcing a self-amplifying feedback loop. Interruption of this loop via POSTN knockdown or using actin polymerization inhibitor Cytochalasin D reduced nuclear beta-catenin levels, confirming the existence of a POSTN-driven outside-in signaling cascade.Using BRAF-mutant melanoma xenograft models, in which either POSTN expression was ablated or beta-catenin-TCF4 interaction was blocked in CAFs, suppressed tumor progression and sensitized melanoma cells to BRAF inhibition. Conversely, POSTN overexpression in CAFs enhanced tumor progression, ECM deposition, including collagen and fibronectin, and resistance to BRAF inhibitors. Importantly, both preclinical models and melanoma patient samples revealed a strong correlation between POSTN expression and nuclear beta-catenin accumulation in CAFs.Together, our findings define an important POSTN-mediated feedback loop that sustains nuclear beta-catenin signaling and reinforces CAF activation. This axis promotes ECM remodeling and contributes to melanoma progression and targeted therapy resistance. Targeting the beta-catenin-TCF4-POSTN circuit represents a promising stroma-targeting strategy to advance targeted therapies against melanoma and improve clinical outcomes.