Abstract 4793: A role for fibroblast derived SASP factors in the activation of non-apoptotic cell death in normal mammary epithelial cells

Abstract

Abstract In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous, biological outcomes. Fibroblasts are one cell type in constant communication with neighboring epithelial cells, and as a result, can alter various cellular parameters. Additionally, fibroblasts are prone to undergo senescence, exemplified by an irreversible cell cycle arrest, in response to a variety of stimuli. Senescent cells exhibit alterations in gene expression and are characterized by substantial changes in their secretome; termed the senescence associated secretory phenotype (SASP). The role of fibroblast derived SASP factors on normal epithelial cells is an area that remains poorly understood. Our studies have found that treatment of normal mammary epithelial cells with conditioned media from senescent fibroblasts (SASP CM) results in a robust programmed cell death. The capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. Interestingly, our data suggest that the cell death caused by SASP CM is dependent on caspase activation, but independent of canonical extrinsic or intrinsic apoptotic pathways. shRNA-mediated reduction of caspase 1 or GSDMD in normal mammary epithelial cells ameliorates the ability of the SASP CM to induce cell death, suggesting that these cells are dying by pyroptosis. Interestingly, breast cancer cells and normal mammary epithelial cells engineered to express oncogenic signals are not susceptible to this SASP CM induced cell death, suggesting that cancer cells have evolved a mechanism to evade SASP CM-mediated pyroptosis.. Taken together, our data reveal a novel relationship between the activation of senescence in stromal cells and the induction of non-apoptotic cell death in normal mammary epithelial cells. Citation Format: Lisa M. Hom, Seunghoon Sun, Jamie Campbell, Ireland Murphy, Shannon Culbert. A role for fibroblast derived SASP factors in the activation of non-apoptotic cell death in normal mammary epithelial cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4793.