The short isoform of MS4A7 is a novel player in glioblastoma microenvironment, M2 macrophage polarization, and tumor progression

作者：Bowen Ni, Guanglong Huang, Runwei Yang, Ziyu Wang, Haimin Song, Kaishu Li, Yunxiao Zhang, Kezhi Wu, Guangwei Shi, Xiran Wang, Jie Shen, Yawei Liu · 发表于：Journal of Neuroinflammation · 年份：2023 · DOI：10.1186/s12974-023-02766-1 · 被引用次数：37 · 研究领域：Glioma Diagnosis and Treatment、Single-cell and spatial transcriptomics、Immune cells in cancer

BACKGROUND: The unique intracranial tumor microenvironment (TME) contributes to the immunotherapy failure for glioblastoma (GBM), thus new functional protein targets are urgently needed. Alternative splicing is a widespread regulatory mechanism by which individual gene can express variant proteins with distinct functions. Moreover, proteins located in the cell plasma membrane facilitate targeted therapies. This study sought to obtain functional membrane protein isoforms from GBM TME. METHODS: With combined single-cell RNA-seq and bulk RNA-seq analyses, novel candidate membrane proteins generated by prognostic splicing events were screened within GBM TME. The short isoform of MS4A7 (MS4A7-s) was selected for evaluation by RT-PCR and western blotting in clinical specimens. Its clinical relevance was evaluated in a GBM patient cohort. The function of MS4A7-s was identified by in vitro and in vivo experiments. MS4A7-s overexpression introduced transcriptome changes were analyzed to explore the potential molecular mechanism. RESULTS: The main expression product, isoform MS4A7-s, generated by exon skipping, is an M2-specific plasma membrane protein playing a pro-oncogenic role in GBM TME. Higher expression of MS4A7-s correlates with poor prognosis in a GBM cohort. In vitro cell co-culture experiments, intracranial co-injection tumorigenesis assay, and RNA-seq suggest MS4A7-s promotes activation of glioma-associated macrophages' (GAMs) PI3K/AKT/GSK3β pathway, leading to M2 polarizat...