| First Author | Wang J | Year | 2026 |
| Journal | Cancer Res Commun | Volume | 6 |
| Issue | 7 | Pages | 1693-1713 |
| PubMed ID | 42295202 | Mgi Jnum | J:389876 |
| Mgi Id | MGI:8394158 | Doi | 10.1158/2767-9764.CRC-25-0682 |
| Citation | Wang J, et al. (2026) BRAF Inhibition-Associated Nuclear Remodeling is Linked to Cancer-Associated Fibroblast Activation. Cancer Res Commun 6(7):1693-1713 |
| abstractText | Cancer-associated fibroblasts (CAFs) display remarkable plasticity, enabling them to adapt to therapeutic and mechanical stress within the tumor microenvironment. In this study, we identify a shared mechanotransduction pathway by which BRAF inhibition and matrix stiffness converge on ROCK-dependent cytoskeletal remodeling, nuclear deformation, and beta-catenin nuclear accumulation in CAFs. Mechanistically, BRAF inhibitors (BRAFi) accelerate RAS-dependent RAF homodimerization and heterodimerization and promote ERK signaling, accompanied by GSK-3beta inactivation and activation of the ROCK pathway. ROCK activation induces actin stress fiber assembly and nuclear deformation. Stiff substrates recapitulate BRAFi-induced actin remodeling and nuclear deformation in CAFs. In both contexts, nuclear remodeling is associated with beta-catenin nuclear accumulation and CAF activation. Functionally, constitutive beta-catenin activation in mouse fibroblasts enhanced CAF-like features in vitro and promoted melanoma growth and matrix remodeling in vivo. Pharmacologic ROCK inhibition blocked both BRAFi- and stiffness-induced nuclear remodeling and beta-catenin accumulation, identifying the ROCK-cytoskeleton-nucleus axis as a mediator of CAF responses to therapeutic and mechanical cues. Collectively, these findings reveal a mechanically tuned signaling mechanism that contributes to CAF activation, supporting ROCK inhibition as a potential strategy to limit tumor-promoting stromal adaptation during targeted therapy. SIGNIFICANCE: This study shows that CAFs respond to BRAF inhibition and mechanical cues via a shared ROCK-cytoskeleton-nucleus pathway. ROCK-dependent nuclear remodeling is associated with beta-catenin accumulation and CAF activation, whereas ROCK inhibition disrupts this response, highlighting a mechanotransduction pathway that may contribute to stromal adaptation during targeted therapy. |
