Abstract

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 (M{varphi}-OC), regulatory/exhausted T cells (Treg-Tex), and monocytes (Mono), respectively. Breast cancer BMs are mostly the M{varphi}-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 M{varphi}-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. HIGHLIGHTSO_LIAnalyses of bone metastases from 6 cancer types revealed three immune archetypes. C_LIO_LIArchetypes diverge on immune trajectories, and features of tumor and stromal cells. C_LIO_LIDominant cell type in each archetype undergoes convergent evolution. C_LIO_LIRegulatory networks converge on osteoclasts and Tregs to drive archetype formation. C_LI Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/593027v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@82cef6org.highwire.dtl.DTLVardef@1e1b021org.highwire.dtl.DTLVardef@1f2881eorg.highwire.dtl.DTLVardef@1c6874a_HPS_FORMAT_FIGEXP M_FIG C_FIG