Abstract 3455: POSTN-driven mechanotransduction sustains β-catenin activity in CAFs to promote melanoma progression and drug resistance

Abstract 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 β-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 β-catenin-mediated transcriptional reprogramming.In this study, we uncover a novel β-catenin-TCF-POSTN regulatory axis that underlies CAF-mediated resistance to BRAF inhibition in melanoma. Specifically, we show that nuclear β-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 β-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 β-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 β-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 β-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 β-catenin accumulation in CAFs.Together, our findings define an important POSTN-mediated feedback loop that sustains nuclear β-catenin signaling and reinforces CAF activation. This axis promotes ECM remodeling and contributes to melanoma progression and targeted therapy resistance. Targeting the β-catenin-TCF4-POSTN circuit represents a promising stroma-targeting strategy to advance targeted therapies against melanoma and improve clinical outcomes. Citation Format: Jie Wang, Bruna DA SILVA SOLEY, Linli Zhou, Yuhang Zhang. POSTN-driven mechanotransduction sustains β-catenin activity in CAFs to promote melanoma progression and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3455.