Tumor-expressed GPNMB orchestrates Siglec-9+TAM polarization and EMT to promote metastasis in triple-negative breast cancer

• 成果类型: Article
• 署名作者: Cao, Thuy Linh Dang; Kawanishi, Kunio; Hashimoto, Sachie; Hengphasatporn, Kowit; Nagai-Okatani, Chiaki; Kimura, Takaharu; Abdelaziz, Mohammed; Shiratani, Rie; Poullikkas, Thanasis; Azmi, Nuriza Ulul; Baba, Masaki; Okita, Yukari; Watanabe, Yukihide; Bando, Hiroko; Yamazaki, Satoshi; Shigeta, Yasuteru; Kuno, Atsushi; Kato, Mitsuyasu
• 署名单位: University of Tsukuba; Showa Medical University; University of Tsukuba; University of Tsukuba; National Institute of Advanced Industrial Science & Technology (AIST); University of Tsukuba; University of Tokyo; Egyptian Knowledge Bank (EKB); Sohag University; University of Tsukuba; Juntendo University; University of Tsukuba
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11676
• DOI: 10.1073/pnas.2503081122
• 发表日期: 2025-09-09
• 关键词: macrophage diversity; cell; progression; engagement

摘要

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 expressing sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9). Tumor-expressed GPNMB promotes monocyte-to-TAM polarization by inducing secondary GPNMB expression in monocytes, establishing a feed-forward amplification loop. GPNMB knockdown in TNBC cells inhibited immunosuppressive TAM subsets, including Siglec-9' and EMT-associated populations, as determined by deconvolution of bulk RNA-seq data using a custom TAM signature matrix derived from publicly available TNBC scRNA-seq datasets. TNBC-derived GPNMB carried alpha 2,3-sialylation, whereas macrophage-derived GPNMB carried alpha 2,6-sialylation, enabling differential Siglec-9 recognition. Elevated GPNMB and Siglec-9 correlated with poor prognosis in TNBCcohorts. Importantly, dual inhibition of Siglec-E (murine Siglec-9 ortholog) and PD-1 reduced tumor stemness, suppressed IL-6-dependent EMT, and limited lung metastasis in vivo. The GPNMB-Siglec-9 axis thus represents a critical glyco-immunological checkpoint driving TAM-mediated metastasis, providing a promising therapeutic target in TNBC.