Abstract 3639: Senescent stromal cells drive breast cancer tumorigenesis

Abstract

Abstract Age is the largest risk factor for the development of cancer, including breast cancer, which is the most frequent malignancy in women. Investigation into how age impacts breast cancer development suggests that both the accumulation of oncogenic mutations within incipient tumor cells and age-related stromal changes conspire to drive tumorigenesis. While numerous physiologic changes arise with age, we posit that the accumulation of p16INKA4 (p16) positive senescent cells, which express various cytokines, chemokines, and enzymes collectively referred to as the senescence-associated secretory phenotype (SASP) contribute to cancer progression. SASP factors not only directly promote the proliferation of tumor cells, but also create an immunosuppressive microenvironment that contributes to robust tumor growth. Immunosuppressive SASP factors are detectable in human breast cancer stroma and high p16 positivity in stromal cells strongly correlates with breast cancer recurrence regardless of subtype. To investigate the role of senescent stroma in mammary tumor development, we crossed MMTV-PyMT (PyMT) transgenic mice that spontaneously develop mammary tumors to INK-ATTAC (INK) mice, which allows selective elimination of p16-positive cells. Depletion of senescent stromal cells in PyMT/INK mice led to significantly delayed mammary tumor onset and changes in various tumor-infiltrating immune cell populations. Analyses of single-cell RNA-sequencing (scRNA-seq) datasets of murine and human mammary tumor/breast cancer samples revealed that senescence is restricted to a cancer-associated fibroblasts (CAFs) subpopulation, which expresses high levels of immune-related and extracellular matrix (ECM)-related SASP factors and shows decreasing abundance in PyMT/INK mice upon the depletion of senescent stroma. Together, these data suggest that senescent CAFs contribute to mammary gland tumorigenesis by modulating tumor immunity and remodeling ECM in the microenvironment. Citation Format: Jiayu (Jennifer) Ye, Ana Paula Delgado, Scott Powers, Sheila Stewart. Senescent stromal cells drive breast cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3639.