Abstract 2956: Chemotherapy-induced adipocyte senescence triggers bone loss through osteoclast activation

Abstract

Abstract Despite breakthroughs in cancer treatment, chemotherapy-induced osteo-toxicity is a major problem that compromises the quality of life and overall survival of cancer patients regardless of cancer type. Recently we demonstrated that chemotherapy-induced senescence drives bone loss by both limiting mineralization of new bone and increasing bone resorption. However, the underlying mechanism of action remains elusive. Therefore, it is critical that we understand the mechanisms that drive these toxicities and develop approaches to mitigate their severity. To establish whether senescent bone resident cells or systemic responses to chemotherapy drove therapy-induced bone loss, we used a vertebral body transplant (vossicle) model. Using this approach, we found that the specific elimination of senescent cells in L4 and L5 donor vossicles (INK-ATTAC) implanted into wildtype mice, protects from chemotherapy-induced bone loss within the vossicles but not the femur of the recipient mice. This demonstrated that chemotherapy-induced senescence in resident bone cells is responsible for bone loss. To determine which bone resident cell(s) underwent senescence in response to chemotherapy and how their gene expression was impacted, we used the p16-CreERT2-tdTomato mouse model and found that chemotherapy triggers senescence in bone marrow adipocytes. Subsequently, we observed that postnatal fat ablation in adipoqCre-inducible DTR transgenic mice (iDTRADQ) prevented chemotherapy-induced bone loss, indicating senescent adipocytes trigger bone loss. Furthermore, we observed chemotherapy-induced bone loss is attributed to RANKL-mediated high osteoclasts activity. Collectively, our data demonstrate that chemotherapy causes senescence in marrow adipocytes which in turn triggers bone loss via RANKL-mediated osteoclasts activation and bone loss can be protected by eliminating senescent cells. Citation Format: Ganesh Kumar Raut, Taylor Malachowski, Taylor Holt, Renata Oliveira, Xianmin Luo, Douglas Faget, Qihao Ren, Sheila Stewart. Chemotherapy-induced adipocyte senescence triggers bone loss through osteoclast activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2956.