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Interrogating glioma-M2 macrophage interactions identifies Gal-9/Tim-3 as a viable target against PTEN-null glioblastoma

Genomic alteration can reshape tumor microenvironment to drive tumor malignancy. However, how PTEN deficiency influences microenvironment-mediated cell-cell interactions in glioblastoma (GBM) remains unclear. Here, we show that PTEN deficiency induces a symbiotic glioma-M2 macrophage interaction to...

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Detalles Bibliográficos
Autores principales: Ni, Xiangrong, Wu, Weichi, Sun, Xiaoqiang, Ma, Junxiao, Yu, Zhihui, He, Xinwei, Cheng, Jinyu, Xu, Pengfei, Liu, Haoxian, Shang, Tengze, Xi, Shaoyan, Wang, Jing, Zhang, Ji, Chen, Zhongping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9269888/
https://www.ncbi.nlm.nih.gov/pubmed/35857445
http://dx.doi.org/10.1126/sciadv.abl5165
Descripción
Sumario:Genomic alteration can reshape tumor microenvironment to drive tumor malignancy. However, how PTEN deficiency influences microenvironment-mediated cell-cell interactions in glioblastoma (GBM) remains unclear. Here, we show that PTEN deficiency induces a symbiotic glioma-M2 macrophage interaction to support glioma progression. Mechanistically, PTEN-deficient GBM cells secrete high levels of galectin-9 (Gal-9) via the AKT-GSK3β-IRF1 pathway. The secreted Gal-9 drives macrophage M2 polarization by activating its receptor Tim-3 and downstream pathways in macrophages. These macrophages, in turn, secrete VEGFA to stimulate angiogenesis and support glioma growth. Furthermore, enhanced Gal-9/Tim-3 expression predicts poor outcome in glioma patients. In GBM models, blockade of Gal-9/Tim-3 signaling inhibits macrophage M2 polarization and suppresses tumor growth. Moreover, α-lactose attenuates glioma angiogenesis by down-regulating macrophage-derived VEGFA, providing a novel antivascularization strategy. Therefore, our study suggests that blockade of Gal-9/Tim-3 signaling is effective to impair glioma progression by inhibiting macrophage M2 polarization, specifically for PTEN-null GBM.