Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression, which disrupts the balance between osteoclasts and osteoblasts and leads to bone lesions. A deeper understanding of the processes mediating this reprogramming could help develop interventions for treating patients with bone metastases. Here, we demonstrated that osteocytes in established breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified osteocytes from mice with breast cancer bone metastasis enriched in senescence, SASP markers, and pro-osteoclastogenic genes. Multiplex in situ hybridization and AI-assisted analysis depicted osteocytes with senescence-associated satellite distension, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. Breast cancer cells promoted osteocyte senescence and enhanced their osteoclastogenic potential in in vitro and ex vivo organ cultures. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that osteocytes undergo pathological reprogramming by breast cancer cells and identify osteocyte senescence as an initiating event triggering lytic bone disease in breast cancer metastases.

中文翻译：

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单细胞转录组分析鉴定了在乳腺癌转移中引发骨破坏的衰老骨细胞


乳腺癌骨转移会增加骨折风险，是女性发病和死亡的主要原因。肿瘤细胞定植后，骨微环境会经历深刻的重新编程以支持癌症进展，从而破坏破骨细胞和成骨细胞之间的平衡并导致骨病变。更深入地了解介导这种重编程的过程可能有助于开发治疗骨转移患者的干预措施。在这里，我们证明了乳腺癌骨转移中的骨细胞会出现过早衰老和独特的衰老相关分泌表型（SASP），有利于骨破坏。单细胞 RNA 测序鉴定出乳腺癌骨转移小鼠的骨细胞富含衰老、SASP 标记和促破骨细胞基因。多重原位杂交和人工智能辅助分析显示小鼠和乳腺癌骨转移患者的骨细胞具有衰老相关的卫星扩张、端粒功能障碍和 p16Ink4a 表达。在体外和离体器官培养中，乳腺癌细胞促进骨细胞衰老并增强其破骨细胞潜能。用 senolytics 清除衰老细胞可抑制乳腺癌骨转移小鼠的骨吸收并保留骨量。这些结果表明，骨细胞经历乳腺癌细胞的病理性重编程，并将骨细胞衰老确定为引发乳腺癌转移中溶骨病的起始事件。