2. Academic Validation
  3. Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression

Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression

  • Cancer Discov. 2024 Jul 1;14(7):1302-1323. doi: 10.1158/2159-8290.CD-23-0426.
Jiayu Ye 1,  John M Baer 2,  Douglas V Faget 1,  Vasilios A Morikis 2,  Qihao Ren 1,  Anupama Melam 1,  Ana Paula Delgado 3,  Xianmin Luo 1,  Satarupa Mullick Bagchi 1,  Jad I Belle 2,  Edward Campos 1 4,  Michael Friedman 1,  Deborah J Veis 5,  Erik S Knudsen 6,  Agnieszka K Witkiewicz 6,  Scott Powers 7,  Gregory D Longmore 2 8 9,  David G DeNardo 2 8 9,  Sheila A Stewart 1 2 8 9
Affiliations

Affiliations

  • 1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
  • 2 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
  • 3 Graduate Program in Genetics, Stony Brook University, Stony Brook, New York.
  • 4 Medical Scientist Training Program, Washington University School of Medicine, St. Louis, Missouri.
  • 5 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
  • 6 Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
  • 7 Department of Pathology and Cancer Center, Renaissance School of Medicine, Stony Brook, New York.
  • 8 ICCE Institute, Washington University School of Medicine, St. Louis, Missouri.
  • 9 Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
PMID: 38683161 DOI: 10.1158/2159-8290.CD-23-0426
Abstract

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast Cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast Cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast Cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324.

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