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 ofmultiple 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 6cancer types and identified 3 ecosystem archetypes characterized by enrichment ofmacrophages/osteoclasts (Macs-OC), regulatory/exhausted T cells (Treg-Tex), and monocytes(Mono), respectively. Breast cancer BMs are mostly the Macs-OC archetype driven by theosteolytic vicious cycle, whereas kidney cancers BMs mainly belong to the Treg-Tex archetypethat lacks osteoclasts. Lung cancers BMs evenly distributed across all archetypes. Furtheranalyses revealed parallel mechanisms of immunosuppression and bone remodeling. Elevatedestrogen signaling distinguishes macrophages in the Macs-OC subtype, which was investigated ina companion study. Together, we elucidated that divergent mechanisms toward bonecolonization and that BMs of different origins can adopt the same mechanism throughconvergent evolution or adaptation.