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

Fengshuo Liu; Yunfeng Ding; Zhan Xu; Xiaoxin Hao; Tianhong Pan; George Miles; Siyue Wang; Yi-Hsuan Wu; Jun Liu; Igor L Bado; Weijie Zhang; Ling Wu; Yang Gao; Liqun Yu; David G Edwards; Hilda L Chan; Sergio Aguirre; Michael Warren Dieffenbach; Elina Chen; Yichao Shen; Dane Hoffman; Luis Becerra Dominguez; Charlotte Helena Rivas; Xiang Chen; Hai Wang; Zbigniew Gugala; Robert L Satcher; Xiang H-F Zhang

doi:10.1016/j.xgen.2025.100888

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

Cell Genom. 2025 Jul 9;5(7):100888. doi: 10.1016/j.xgen.2025.100888. Epub 2025 May 23.

Authors

Fengshuo Liu¹, Yunfeng Ding², Zhan Xu², Xiaoxin Hao², Tianhong Pan³, George Miles⁴, Siyue Wang⁵, Yi-Hsuan Wu¹, Jun Liu², Igor L Bado², Weijie Zhang², Ling Wu², Yang Gao², Liqun Yu², David G Edwards², Hilda L Chan⁶, Sergio Aguirre⁷, Michael Warren Dieffenbach⁸, Elina Chen⁹, Yichao Shen⁷, Dane Hoffman¹, Luis Becerra Dominguez⁵, Charlotte Helena Rivas¹, Xiang Chen², Hai Wang², Zbigniew Gugala¹⁰, Robert L Satcher¹¹, Xiang H-F Zhang¹²

Affiliations

¹ Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Cancer and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
² Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
³ Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
⁴ Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁵ Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Immunology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁶ Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Cancer and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁸ Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Development, Disease Models, and Therapeutics, Baylor College of Medicine, One Baylor Plaza, Houston TX 77030, USA.
⁹ College of Natural Sciences, University of Texas at Austin, 110 Inner Campus Drive, Austin, TX 78706, USA.
¹⁰ Department of Orthopedic Surgery and Rehabilitation, University of Texas Medical Branch, Galveston, TX, USA.
¹¹ Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: rlsatcher@mdanderson.org.
¹² Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: xiangz@bcm.edu.

PMID: 40412393
DOI: 10.1016/j.xgen.2025.100888

Abstract

Bone is a common site for metastasis of solid cancers. The diversity of histological and molecular characteristics of bone metastases (BMs) remains poorly studied. Here, we performed single-cell RNA sequencing on 42 BMs from eight cancer types, identifying three distinct ecosystem archetypes, each characterized by an enrichment of specific immune cells: macrophages/osteoclasts, regulatory/exhausted T cells, or monocytes. We validated these archetypes by immunostaining on tissue sections and bioinformatic analysis of bulk RNA sequencing/microarray data from 158 BMs across more than 10 cancer types. Interestingly, we found only a modest correlation between the BM archetypes and the tissues of origin; BMs from the same cancer type often fell into different archetypes, while BMs from different cancer types sometimes converged on the same archetype. Additional analyses revealed parallel immunosuppression and bone remodeling mechanisms, some of which were experimentally validated. Overall, we discovered unappreciated heterogeneity of BMs across different cancers.

Keywords: bone metastases; convergent and divergent evolution; immune archetypes; immune evasion; immunosuppression; single-cell RNA sequencing; tumor microenvironment.

MeSH terms

Bone Neoplasms* / genetics
Bone Neoplasms* / pathology
Bone Neoplasms* / secondary
Humans
Macrophages / metabolism
Neoplasms* / genetics
Neoplasms* / pathology
Osteoclasts / metabolism
Osteoclasts / pathology
Single-Cell Analysis* / methods
Tumor Microenvironment