A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Liyang Zhang
Department of Medicine, The University of Oklahoma Health Sciences Center
Jingxuan Yang
Department of Medicine, The University of Oklahoma Health Sciences Center
Zhijun Zhou
The Institute for Advanced Studies, Wuhan University, 299 Bayi Road, Wuhan 430072, China
Yu Ren
Department of Medicine, The University of Oklahoma Health Sciences Center
Bo Chen
Anliu Tang
Department of Gastroenterology, The Third Xiangya Hospital of Central South University
Kailiang Zhang
Department of Medicine, The University of Oklahoma Health Sciences Center
Chuntao Li
Department of Medicine, The University of Oklahoma Health Sciences Center
Hongshu Zhou
Department of Neurosurgery, Xiangya Hospital, Central South University
Kar-Ming Fung
Department of Pathology, The University of Oklahoma Health Sciences Center
Chao Xu
Chunsheng Kang
Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-Trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education
James D. Battiste
Department of Neurosurgery, The University of Oklahoma Health Sciences Center
Michael S. Bronze
Department of Medicine, The University of Oklahoma Health Sciences Center
Courtney W. Houchen
Department of Medicine, The University of Oklahoma Health Sciences Center
Zhixiong Liu
Department of Neurosurgery, Xiangya Hospital, Central South University
Ian F. Dunn
Department of Neurosurgery, The University of Oklahoma Health Sciences Center
Webster K. Cavenee
Department of Medicine, University of California at San Diego
Min Li