A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells

Abstract

In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media (CM) from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D (GSDMD)-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells.

Exploring the emerging bidirectional association between inflamm‐aging and cellular senescence in organismal aging and disease

“…111 Exposure to conditioned media derived from SASP-expressing senescent fibroblasts induced pyroptosis in mammary epithelial cells. 112 A novel SASP component (Ptk7) released by senescent fibroblasts has been identified that deregulates stem cell activity and differentiation, resulting in impaired crypt formation in intestinal organoids and indicating a unique role of SASP in augmenting tissue dysfunction in aging and disease. 113 Similarly, another recent study noted that extracellular vesicles secreted by SASP of senescent human osteoarthritis-derived chondrocytes induce a senescent phenotype in chondrocytes, and synovial and bone cells leading to the development of an inflammatory and degenerative joint environment.…”

“…T cell senescence was accompanied by SASP that exacerbated neuroinflammation and tumorigenesis in experimental mice 111 . Exposure to conditioned media derived from SASP‐expressing senescent fibroblasts induced pyroptosis in mammary epithelial cells 112 . A novel SASP component (Ptk7) released by senescent fibroblasts has been identified that deregulates stem cell activity and differentiation, resulting in impaired crypt formation in intestinal organoids and indicating a unique role of SASP in augmenting tissue dysfunction in aging and disease 113 .…”