Single cell profiling of bone metastasis ecosystems from multiple cancer types reveals convergent and divergent mechanisms of bone colonization

Bone represents congenial soil for metastatic seeds and is frequently affected by metastasis of multiple cancer types. The histological and molecular characteristics of bone metastases (BMs) are diverse but poorly understood. Herein, we performed single-cell RNA-seq on 34 BMs from 6 cancer types and identified 3 ecosystem archetypes characterized by enrichment of macrophages/osteoclasts (Mφ-OC), regulatory/exhausted T cells (Treg-Tex), and monocytes (Mono), respectively. Breast cancer BMs are mostly the Mφ-OC archetype driven by the osteolytic vicious cycle, whereas kidney cancers BMs mainly belong to the Treg-Tex archetype that lacks osteoclasts. Lung cancers BMs evenly distributed across all archetypes. Further analyses revealed parallel mechanisms of immunosuppression and bone remodeling. Elevated estrogen signaling distinguishes macrophages in the Mφ-OC subtype, which was investigated in a companion study. Together, we elucidated that divergent mechanisms toward bone colonization and that BMs of different origins can adopt the same mechanism through convergent evolution or adaptation. In this study, patient samples were collected from MD Anderson Cancer Center in collaboration with Dr. Robert L Satcher. The protocols for the collection and use of human bone metastasis samples were performed following the Declaration of Helsinki and approved by the Institutional Review Boards at Baylor College of Medicine (H-49396), The University of Texas MD Anderson Cancer Center (PA15-0225), and the University of Texas Medical Branch (H-46675). All the patients have provided written informed consent on the use of their samples for research purposes when undergoing orthopedic surgery. The selection of patient samples was driven by clinical necessity, focusing on individuals requiring surgical intervention. However, there were no restrictions on patient selection beyond this clinical consideration. Our sample collection was comprehensive, encompassing both single cell sequencing and the generation of tissue sections for pathology studies as dictated by clinical need. Specifically, we acquired bone tissue regions from 34 patients, encompassing both metastasized tumors and bone tissues. These samples were predominantly sourced from long bones within the human body. Additionally, we obtained 5 healthy individual human bone marrow from Lonza (Catalog#: 1M-105). This approach allowed us to acquire a diverse range of samples tailored to the specific requirements of the patients, ultimately contributing to the comprehensiveness of our study. UPDATE: [Sep-29-2025] The titles of a subset of Samples were updated. The former titles are included in the Sample description field. The raw and processed data associated with each GSMxxx have not changed.

骨骼是转移性肿瘤细胞定植的适宜土壤，多种癌症类型常发生骨转移（bone metastases, BMs）。骨转移的组织学与分子特征多样，但目前对其认知仍较为有限。本研究对6种癌症类型的34例骨转移标本开展单细胞RNA测序，鉴定出3种生态系统原型，分别以巨噬细胞/破骨细胞（macrophages/osteoclasts, Mφ-OC）、调节性/耗竭性T细胞（regulatory/exhausted T cells, Treg-Tex）以及单核细胞（monocytes, Mono）的富集为特征。乳腺癌骨转移多为溶骨性恶性循环驱动的Mφ-OC原型，而肾癌骨转移主要属于缺乏破骨细胞的Treg-Tex原型；肺癌骨转移则均匀分布于所有原型中。进一步分析揭示了免疫抑制与骨重塑的并行作用机制。Mφ-OC亚型中的巨噬细胞存在雌激素信号通路激活特征，相关机制已在配套研究中展开探索。综上，本研究阐明了肿瘤细胞骨定植的多样化机制，且不同起源的骨转移可通过趋同进化或适应性改变共享相同的作用机制。本研究的患者标本采集自德克萨斯大学MD安德森癌症中心，合作方为Robert L Satcher博士。人骨转移标本的采集与使用流程均遵循《赫尔辛基宣言》，并经贝勒医学院（伦理审批号：H-49396）、德克萨斯大学MD安德森癌症中心（伦理审批号：PA15-0225）以及德克萨斯大学医学分部（伦理审批号：H-46675）的伦理审查委员会批准。所有患者在接受骨科手术时，均已签署书面知情同意书，同意其标本用于科研用途。患者标本的筛选基于临床需求，聚焦于需要手术干预的个体，除临床考量外无额外筛选限制。本次样本采集覆盖全面，根据临床需求同时包含单细胞测序样本与病理研究所需的组织切片。具体而言，我们从34例患者中获取了骨组织区域，涵盖转移瘤与骨组织本身，这些样本主要来源于人体长骨。此外，我们从龙沙（Lonza）公司获取了5份健康人骨髓标本（货号：1M-105）。本采样策略覆盖了多样化的样本类型，适配患者的具体临床需求，最终保障了本研究的全面性。更新：[2025年9月29日] 部分样本的标题已完成更新，原标题已纳入样本描述字段。与每个GSMxxx编号关联的原始数据及处理后数据均未发生变更。