biostudies-literatureDang Cao TLMEXT | Japan Society for the Promotion of ScienceMEXT | Japan Science and Technology Agency (JST)MEXT | Japan Society for the Promotion of Science (JSPS)Ministry of Education, Culture, Sports, Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology (MEXT)MEXT | Japan Science and Technology Agencye2503081122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12435292biostudies-literatureUnknown122(36)Metastasis remains the leading cause of cancer-related mortality, driven by complex interactions within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a pivotal role in metastatic progression, yet their molecular diversity and upstream regulators remain poorly defined. Glycoprotein nonmetastatic melanoma protein B (GPNMB), overexpressed in subsets of tumors including triple-negative breast cancer (TNBC), is implicated in epithelial-mesenchymal transition (EMT) and cancer stemness. Recent single-cell RNA sequencing (scRNA-seq) identified GPNMB as a marker of immunosuppressive TAMs associated with poor prognosis, but its mechanistic role in TNBC has remained unclear. Coculturing monocytic cells with three-dimensional TNBC spheres induced GPNMB⁺ TAMs expProceedings of the National Academy of Sciences of the United States of AmericaTumor-expressed GPNMB orchestrates Siglec-9<sup>+</sup> TAM polarization and EMT to promote metastasis in triple-negative breast cancer.PMC12435292JPMJST2052JPMJCR20B3JP24K0225723H04879Watanabe YKimura TAzmi NUNagai-Okatani CDang Cao TLPoullikkas TBaba MKawanishi KAbdelaziz MShiratani ROkita YKuno AHashimoto SKato MShigeta YHengphasatporn KBando HYamazaki SfalseTumor-expressed GPNMB orchestrates Siglec-9<sup>+</sup> TAM polarization and EMT to promote metastasis in triple-negative breast cancer.Metastasis remains the leading cause of cancer-related mortality, driven by complex interactions within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a pivotal role in metastatic progression, yet their molecular diversity and upstream regulators remain poorly defined. Glycoprotein nonmetastatic melanoma protein B (GPNMB), overexpressed in subsets of tumors including triple-negative breast cancer (TNBC), is implicated in epithelial-mesenchymal transition (EMT) and cancer stemness. Recent single-cell RNA sequencing (scRNA-seq) identified GPNMB as a marker of immunosuppressive TAMs associated with poor prognosis, but its mechanistic role in TNBC has remained unclear. Coculturing monocytic cells with three-dimensional TNBC spheres induced GPNMB⁺ TAMs exp2025-01-01T00:00:00Z2025 Sep2026-07-17T01:10:10.358Z2026-07-12T03:12:51.03ZS-EPMC124352924089292010.1073/pnas.2503081122