Highly plastic macrophage niches orchestrate acquired quiescence and reactivation in breast-cancer bone metastasis
Year: 2026
Type: preprint
Abstract: Recurrence and metastasis remain major causes of cancer mortality, sustained by therapy-resistant micrometastatic cells. Bone is a frequent site of breast-cancer relapse, yet the cues that reawaken disseminated cells remain poorly defined. We identify a previously unrecognized, highly plastic CXCL16⁺ macrophage population that integrates tumor-associated macrophage programs found in distant metastatic sites such as lung and brain with non-tumor disease–associated traits in bone marrow. These CXCL16⁺ macrophages establish a transient niche that restrains disseminated cancer-cell proliferation. Single-cell transcriptomics delineate functional remodeling of myeloid niches within the bone metastatic microenvironment: a CXCL16⁺ macrophage niche that transiently constrains metastatic growth, and G-CSF⁺ macrophage and neutrophil niches that reignite tumor outgrowth. In primary tumors, cancer-associated fibroblasts (CAFs) aberrantly secrete G-CSF in response to cancer-cell signals, expanding G-CSF-receptor–positive subset of cancer cells with high metastatic potential. In advanced human bone metastases, CXCL16⁺ macrophages localize to CAF-rich stroma but are excluded from cancer-cell clusters, indicating immune evasion. Together, these findings uncover CAF–bone-marrow cross-talk as a therapeutic target linking stromal inflammation, immune remodeling, and metastatic progression.
Authors: Yasuto Takeuchi, Huazi Zhang, Takahiko Murayama, Tsunaki Hongu, Kazuhiro Ikeda, Kuniko Horie, Satoshi Inoue, Masao Yano, Masahiko Tanabe, Yuki Kurokawa, Hirofumi Terakawa, Noriyuki Inaki, Kei-ichiro Tada, Etsuo A. Susaki, Eishu Hirata, Shu-ichi Tsukamoto, Masafumi Horie, Hiroshi Watarai, Kazuo Okamoto, Shinya Sato, Yohei Miyagi, Fumio Arai, Toshio Suda, Arinobu Tojo, Koji Okamoto, Hans Clevers, Tuomas Tammela, Noriko Gotoh
Institutions: Kanazawa University, Cancer Research Institute of Kanazawa University, Saitama Medical University, The University of Tokyo, Nihon University, Juntendo University, National Cancer Center Hospital East, Kobe University, Environmental Stress Research Center, Kanazawa University, Teikyo University, Kanagawa Cancer Center, Kyushu University, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, Institute of Science Tokyo, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Memorial Sloan Kettering Cancer Center
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G2380293117, G4600361218, G4695319980, G4953915240, Elucidation of recurrence and metastasis by using a mouse mammary tumor model and development of novel preventive strategies, Elucidation of the molecular mechanism of recurrent and metastatic cancer using a breast cancer mouse model and establishment of a preventive method, G6895429820, G7992780193, Single-cell level integrated elucidation of genomic gene mutation heterogeneity and stem cell hierarchy in breast cancer primary and metastasis, 女性難治がんのPDXモデルを用いたがん微小環境を標的とした革新的診断治療法の構築, Integrated Elucidation of Genome Mutation Heterogeneity and Stem Cell Hierarchy in Breast Cancer at the Single-Cell Level
OpenAlex ID: W7204966531