Abstract 2592: The osteoblastic microenvironment determines the fate of breast cancer cells disseminated in the bone marrow

Abstract Bone is the most common destination for metastatic breast cancer cells. When cancer cells disseminate to the bone, they may either colonize or settle into a quiescent state, depending on their interaction with the bone microenvironment. In this study, we elucidated how the differentiation status of the osteoblastic microenvironment determines the fate of cancer cells disseminated in the bone marrow. We analyzed clinical survival data and demonstrated that luminal-like cancer cells with high Runt-related transcription factor 2 (RUNX2) expression exhibited an increased risk of bone metastases in breast patients. By using RUNX2-overexpressing cancer cells as bone-tropic seeds and establishing various osteoblastic microenvironments with different differentiation statuses in vitro and in vivo, we observed that both luminal-like and basal-like cancer cells remained quiescent as disseminated tumor cells (DTCs) or micrometastases within an inactive osteoblastic microenvironment. In contrast, luminal-like cancer cells colonize the bone within both nonmineralized and mineralized active osteoblastic (osteogenic) microenvironments. Basal-like cancer cells, however, remained quiescent within highly mineralized osteogenic microenvironment but colonized bone in a nonmineralized osteogenic niche rich in nonmineralized bone matrix (osteoid). In the active microenvironments, well-differentiated osteoblasts were observed to be responsible for recruiting cancer cells, whereas the nonmineralized bone matrix supported the proliferation of both luminal-like and basal-like cancer cells, with luminal-like cells gaining additional growth advantages from well-differentiated osteoblasts. Furthermore, we explored the possibility that activation of the osteoblastic microenvironment due to abnormal bone metabolism and fluctuating estrogen levels reactivate quiescent DTCs or micrometastases, leading to increased risk of bone metastasis. Additionally, in a supportive osteogenic microenvironment, both cancer cells and well-differentiated osteoblasts were found to contribute to the activation of osteoclasts, resulting in the development of osteolytic lesions. Thus, this study provides a comprehensive explanation for the divergent outcomes of disseminated cancer cells in the bone, whether they colonize the bone or become dormant, and suggests promising therapeutic strategies to block the reactivation of quiescent tumor cells. Citation Format: Hong-Li Wang, Xiao-Min Yue, Rui Zhang, Yu-Fan Huang, Rong Meng, Xiao-Qing Li. The osteoblastic microenvironment determines the fate of breast cancer cells disseminated in the bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2592.