2. Academic Validation
  3. Bone-derived Osterix+ osteolineage cells are a source of tumor-promoting myofibroblastic cancer-associated fibroblasts in breast cancer

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

  • Nat Commun. 2026 Jun 11. doi: 10.1038/s41467-026-73980-7.
Giulia Furesi 1,  Carisa Zeng 2 3,  Emily M Eul 1,  Jennifer Zarrer 4,  Deborah J Veis 2 5 6 7,  Jiayu Ye 8,  Vasilios A Morikis 5,  Taylor Malachowski 8,  Darya Khantakova 2,  Alina Ulezko Antonova 2,  Anupama Melam 8,  Marco Colonna 2,  Eric Hesse 4,  Hanna Taipaleenmäki 4,  Gregory D Longmore 5 6,  Sheila A Stewart 5 6 8,  Maxim N Artyomov 2 9,  Roberta Faccio 10 11 12
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 3 Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 4 Institute of Musculoskeletal Medicine, Musculoskeletal University Center Munich, University Hospital, LMU Munich, Munich, Germany.
  • 5 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 6 Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
  • 7 Shriners Hospitals for Children, St. Louis, Missouri, USA.
  • 8 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 9 Bursky Center for Human Immunology and Immunotherapy Programs, School of Medicine, Washington University in St. Louis, St Louis, MO, USA.
  • 10 Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. [email protected].
  • 11 Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA. [email protected].
  • 12 Shriners Hospitals for Children, St. Louis, Missouri, USA. [email protected].
PMID: 42277024 DOI: 10.1038/s41467-026-73980-7
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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