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

ABSTRACT: Cancer-associated fibroblasts (CAFs) are major regulators of breast cancer (BC) progression and therapeutic resistance, yet the extent to which CAF heterogeneity is dictated by distinct cellular origins remains unresolved. 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. Together, these findings identify a distinct bone-derived osteolineage cell that gives rise to OsteoLin-myCAFs and is linked to adverse clinical outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE292888 | GEO | 2026/05/11

REPOSITORIES: GEO

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Project description:Studies from global loss-of-function mutants suggest that alternative NF-kB downstream of NF-kB inducing kinase (NIK) is a cell-intrinsic negative regulator of osteogenesis. However, the interpretation of the osteoblast and/or osteocyte contribution to the bone phenotype is complicated by simultaneous osteoclast defects in these models. Therefore, we turned to a transgenic mouse model to investigate the direct role of NIK in the osteolineage. Osx-Cre;NT3 animals (NT3-Cre+), which bear a constitutively active NIK allele (NT3) driven by Osx-Cre, were compared to their Cre-negative, Control (Ctrl) littermates. NT3-Cre+ mice had elevated serum P1NP and CTX levels. Despite this high turnover state, microCT showed that constitutive activation of NIK resulted in a net increase in basal bone mass in both cortical and cancellous compartments. Furthermore, NT3-Cre+ mice exhibited a greater anabolic response following mechanical loading compared to controls. We next performed RNA-Seq on non-loaded and loaded tibiae to elucidate possible mechanisms underlying the increased bone anabolism seen in NT3-Cre+ mice. Hierarchical clustering revealed two main transcriptional programs: one loading-responsive and the other NT3 transgene-driven. Gene ontology (GO) analysis indicated a distinct upregulation of receptor, kinase and growth factor activities including Wnts, as well as a calcium-response signature in NT3-Cre+ limbs. The promoters of these GO-term associated genes, including many known to be bone-anabolic, were highly enriched for multiple kB recognition elements (kB-RE) relative to the background frequency in the genome. The loading response in NT3-Cre+ mice substantially overlapped (>90%) with Ctrl. Surprisingly, control animals had 10-fold more differentially expressed genes (DEGs) in response to loading. However, most top DEGs shared between genotypes had a high incidence of multiple kB-RE in their promoters. Therefore, both transcriptional programs (loading-responsive and NT3 transgene-driven) are modulated by NF-kB. Our studies uncover a previously unrecognized role for NF-kB in the promotion of both basal and mechanically-stimulated bone formation.

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

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