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 BC models in female mice and biopsies from women with BC, we show that bone-resident Osx+ cells are recruited to primary tumors. These cells 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.
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Acknowledgements
We thank Dr. Simone Brioschi for sharing immunofluorescence protocols. We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for assistance with genomic analysis. We thank the Musculoskeletal Histology Core of the Musculoskeletal Research Center, the Washington University Bright Institute Molecular Imaging Center, and the Siteman Flow Cytometry Core for technical support. We thank the St. Louis Breast Tissue Registry at Washington University School of Medicine, Department of Surgery, for assistance in obtaining tissue samples. Schema figures were created in BioRender (Furesi, G. (https://BioRender.com/rpuownu).
Funding
This research was supported by grants from the National Institutes of Health (NIH) Grants R01AR066551 (to R.F.), R01CA270030 (to R.F.), and R01CA235096 (to R.F.), grants from Shriners Hospital 85170 and P19-07408 CR (to R.F.), the Siteman Investment Program, Siteman Cancer Center (Pre-R01 Program to R.F.) and the Foundation for Barnes-Jewish Hospital (3770 and 4642). G.F. was supported by Cancer Research Institute Irvington postdoctoral fellowship CRI5013, E.M.E. was supported by T32GM139774 and F31CA284858, T.M. was supported by T32 AR060719, and J.Y. was supported by T32CA113275 and F31CA271721-01. GDL was supported by NIH grant R01 CA254060 and V.M. by F32CA27521. S.A.S. was supported by NIH grants R01 AG059244, CA217208, and CA282810. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014, is the awarding and administering acquisition office, and this was supported in part by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program, under award No. BC181712. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. This work was also supported by the Siteman Cancer Center Investment Program (NCI Cancer Center Support Grant P30CA091842), Fashion Footwear Association of New York, and the Alvin J. Siteman Cancer Center Siteman Investment Program (supported by The Foundation for Barnes-Jewish Hospital, Cancer Frontier Fund, to S.A.S.). H.T. acknowledges funding from the German Federal Ministry of Education and Research (BMBF) within ERA-NET TRANSCAN-3 (grant number 01KT2303), and German Research Foundation (DFG; grant numbers TA 1152/1-2 and TA 1154/2-2). The Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center from the National Center for Research Resources (NCRR), a component of NIH, and NIH Roadmap for Medical Research. The Musculoskeletal Histology Core of the Musculoskeletal Research Center is supported by the NIH P30 Grants AR057235 and P30 AR074992. The Washington University Bright Institute, Molecular Imaging Center is supported by the NIH P50 CA94056ADD. The Siteman Flow Cytometry Core is supported by NCI Cancer Center support grant P30 CA91842 and P30CA091842. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.
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During the period this work was done, the Longmore laboratory received funding from Pfizer-CTI, San Diego, CA, and Centene Corporation, St. Louis, MO. M. Colonna is a member of the Vigil Neuroscientific advisory board and a consultant for Cell Signaling Technology. All other authors declare that they have no conflict of interest.
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Furesi, G., Zeng, C., Eul, E.M. et al. Bone-derived Osterix+ osteolineage cells are a source of tumor-promoting myofibroblastic cancer-associated fibroblasts in breast cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73980-7
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DOI: https://doi.org/10.1038/s41467-026-73980-7
