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July 17th, 2025
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Department of Molecular Reproduction, Development and Genetics; Indian Institute of Science, Bangalore, India
cancer biology
biorxiv

Stromal LOX/FAK/beta catenin pathway locks mammary fibroblasts into a tumor-promoting myCAF state

Gandhi, A.Open in Google Scholar•Beri, D.Open in Google Scholar•Pally, D.Open in Google Scholar•Manjunath, S.Open in Google Scholar•Humcha, S.Open in Google Scholar•Rangarajan, A.Open in Google Scholar•Bhat, R.Open in Google Scholar•Tatu, U.Open in Google Scholar•Kumar, R. V.Open in Google Scholar•Kondaiah, P.Open in Google Scholar

Background: Cancer-associated fibroblasts (CAFs) sustain tumor progression, yet the soluble cues that maintain their myofibroblast (myCAF) state are poorly defined. Transforming growth factor beta; (TGF beta) is a canonical CAF activator. This study aims to identify TGF beta-induced secreted mediators that reinforce the myCAF phenotype in breast cancer and map the downstream signaling cascade. Methods and Results: Secretome profiling of primary patient-derived myCAFs and human mammary fibroblasts (HMF3s) engineered to over-express TGF beta1 revealed 20 extracellular matrix remodelers shared exclusively by both activated states; lysyl oxidase (LOX) was the top-ranked hit. LOX knockdown abrogated TGF beta driven alpha smooth muscle actin (alpha SMA) induction, collagen gel contraction and migration in HMF3s, and reduced constitutive alpha SMA and beta catenin in myCAFs. Mechanistically, TGF beta; upregulated LOX, which activated focal adhesion kinase (FAK), leading to p38 MAPK- and Akt-mediated Ser9 phosphorylation (inactivation) of GSK3 beta; and consequent beta catenin stabilization. In HCC1806-luciferase orthotopic xenografts, CAFs accelerated tumor growth, whereas LOX-deficient CAFs lost this pro-tumoral effect. Conclusion: LOX is a pivotal autocrine effector of TGF beta; that locks breast CAFs into a pro-tumoral myCAF state via a LOX/FAK/GSK3beta/beta catenin axis. Targeting stromal LOX may disrupt CAF activation and curb breast cancer progression.

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