Bone-derived osterix+ osteolineage cells are a source of tumor-promoting myofibroblastic cancer-associated fibroblasts in breast cancer

Here, we identify bone-derived Osterix+ (Osx) osteolineage cells as a source of CAFs in BC. Using lineage tracing, BC models and patient biopsies, we show that bone-resident Osx+ cells are recruited to primary tumors, where they preferentially differentiate into a myofibroblastic CAF subset with unique osteolineage identity (OsteoLin-myCAFs).

OsteoLin-myCAFs are transcriptionally and functionally distinct from other subsets, exhibit enhanced extracellular matrix remodeling and pronounced pro-tumorigenic activity. Mechanistically, Osx drives expression of matrix-remodeling programs, including MMP13, which supports tumor growth. Cross-species analyses show a conserved 54-gene osteolineage signature in myCAFs from human BC samples, strongly associated with poor survival.