Abstract 137: Abrogating therapy induced senescence driven bone loss to improve quality of life

Abstract

Abstract Despite the central role chemotherapy plays in prolonging survival, the toxicities associated with its use can negatively impact quality of life and in some cases, be so severe that patients forego further life preserving treatments. Therefore, it is critical that we understand the mechanisms that drive these toxicities and develop approaches to mitigate their severity. Recently we demonstrated that chemotherapy-induced senescence drives bone loss by both limiting mineralization of new bone and increasing bone resorption. To establish whether senescent bone resident cells or systemic responses to chemotherapy drove therapy-induced bone loss, we used a vossicle model in which neonatal vertebral bones (L4 and L5) were transplanted from 4-day old wildtype or INKATTAC pups (allow to selectively kill senescent cells) into wildtype or INKATTAC adult mice. Using this approach, we found that the elimination of senescent cells in donor vossicles protects from chemotherapy-induced bone loss, indicating that senescent bone resident cells are responsible for therapy-induced bone loss. To understand the mechanism(s) that contributed to therapy-induced bone loss, we used scRNA-seq to determine which bone resident cells underwent senescence in response to chemotherapy and how their gene expression was impacted. Using this approach, we found that adipocytes, fibroblast, chondrocytes and osteoblasts underwent senescence as evidenced by expression of p16, p21 and loss of Mki67 and displayed evidence of a senescence associated secretory phenotype (SASP), which we postulate contributes to therapy-induced bone loss. Collectively, our data indicated that chemotherapy causes bone loss via senescence and can be protected by eliminating senescent cells. Citation Format: Ganesh Kumar Raut, Zhangting Yao, Tom Cole, Xainmin Luo, Qihao Ren, Sheila A. Stewart. Abrogating therapy induced senescence driven bone loss to improve quality of life [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 137.