单细胞转录组分析识别出引发乳腺癌转移中骨破坏的衰老骨细胞

IF 12.5 1区 医学 Q1 ONCOLOGY
Japneet Kaur, Manish Adhikari, Hayley M Sabol, Aric Anloague, Sharmin Khan, Noriyoshi Kurihara, Marta Diaz-delCastillo, Christina Møller Andreasen, C Lowry Barnes, Jeffrey B Stambough, Michela Palmieri, Olivia Reyes-Castro, Jennifer Zarrer, Hanna Taipaleenmäki, Elena Ambrogini, Maria Almeida, Charles O'Brien, Intawat Nookaew, Jesus Delgado-Calle
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引用次数: 0

摘要

乳腺癌骨转移会增加骨折风险,是妇女发病和死亡的主要原因。肿瘤细胞定植后,骨微环境会发生深刻的重编程,以支持癌症的进展,从而破坏破骨细胞和成骨细胞之间的平衡,导致骨病变。深入了解介导这种重编程的过程有助于开发治疗骨转移患者的干预措施。在这里,我们证明了已确立的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),这种表型有利于骨破坏。单细胞 RNA 测序发现,乳腺癌骨转移小鼠的骨细胞富含衰老、SASP 标记和促破骨细胞生成基因。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存在衰老相关的卫星扩展、端粒功能障碍和 p16Ink4a 表达。乳腺癌细胞促进了骨细胞的衰老,并增强了其在体外和体内器官培养中的破骨细胞生成潜能。用衰老剂清除衰老细胞可抑制骨吸收,保护乳腺癌骨转移小鼠的骨量。这些结果表明,乳腺癌细胞会对成骨细胞进行病理重编程,并确定成骨细胞衰老是引发乳腺癌骨转移中溶解性骨病的起始事件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Single-cell Transcriptomic Analysis Identifies Senescent Osteocytes that Trigger Bone Destruction in Breast Cancer Metastasis.

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.

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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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