A zinc transporter drives glioblastoma progression via extracellular vesicles- reprogrammed microglial plasticity

• 成果类型: Article
• 署名作者: Zhang, Liyang; Yang, Jingxuan; Zhou, Zhijun; Ren, Yu; Chen, Bo; Tang, Anliu; Zhang, Kailiang; Li, Chuntao; Zhou, Hongshu; Fung, Kar - Ming; Xu, Chao; Kang, Chunsheng; Battiste, James D.; Bronze, Michael S.; Houchen, Courtney W.; Liu, Zhixiong; Dunn, Ian F.; Cavenee, Webster K.; Li, Min
• 署名单位: University of Oklahoma System; University of Oklahoma Health Sciences Center; University of Oklahoma System; University of Oklahoma Health Sciences Center; Central South University; Central South University; University of Oklahoma System; University of Oklahoma Health Sciences Center; University of Oklahoma System; University of Oklahoma Health Sciences Center; Tianjin Medical University; University of Oklahoma System; University of Oklahoma Health Sciences Center; University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14300
• DOI: 10.1073/pnas.2427073122
• 发表日期: 2025-05-06
• 关键词: tumor; expression; macrophage; activation; phenotype; reflect; marker; GROWTH; trem-1; cells

摘要

Glioblastoma (GBM) is the most aggressive form of brain cancer, with limited therapeutic options. While microglia contribute to GBM progression, the mechanisms by which they foster a protumorigenic immune environment remain poorly understood. We identify the zinc transporter Zrt-And Irt-Like Protein 4 (ZIP4) as a pivotal regulator of the GBM immune landscape. In orthotopic mouse models, ZIP4 drives tumor growth and behavioral changes. Mechanistically, ZIP4 modulates microglial plasticity through tumor-derived extracellular vesicles carrying triggering receptor expressed on myeloid cells-1 (TREM1), a process regulated by the zinc-dependent transcription factor Zinc Finger E-box Binding Homeobox 1 in GBM cells. TREM1 enhances microglial plasticity through the spleen associated tyrosine kinase-Pyruvate dehydrogenase kinase-signal transducer and activator of transcription 3 (SYK-PDK-STAT3) signaling axis, ultimately promoting an immune environment favorable to tumor progression. ZIP4 depletion or TREM1 inhibition attenuates tumor growth and behavioral effects in vivo by disrupting the tumor-microglia interaction. These findings establish ZIP4 as a key modulator of the GBM immune landscape and suggest a promising therapeutic target to counteract microglia-mediated tumor progression.