Abstract
Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by GBM stem cells (GSCs). The interplay between GSCs and the immunosuppressive microglia plays crucial roles in promoting malignant growth of GBM, however, the molecular mechanisms underlying this crosstalk are incompletely understood. We performed RNA sequencing to explore the mechanism by which periostin (POSTN) regulates GSCs and microglia. The biological function of POSTN in GBM development was confirmed in vitro and in vivo. Specifically, tumorsphere formation assay, proliferation analysis, migration assays, enzyme-linked immunosorbent assay, immunoblotting, and intracranial mouse model were performed. We identified POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVβ3/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/β-catenin/FOS like antigen 1 (FOSL1) pathway. In addition to its GSC intrinsic effects, POSTN is able to recruit microglia and upregulate cluster of differentiation 70 (CD70) expression through PI3K/AKT/nuclear factor-kappa B (NFκB) pathway in microglial cells, which in turn promotes the Treg development and functionality, and generates an immunosuppressive tumor microenvironment. Inhibition POSTN disrupts the GSC maintenance, inhibits recruitment of immunosuppressive microglial, reduces Treg development and function, and suppresses GBM growth, suggesting that targeting POSTN may effectively improve GBM treatment. In conclusion, our study defined POSTN as a key regulator in mediating the molecular crosstalk between GSCs and immune-suppressive Microglia in the tumor microenvironment in GBM. POSTN activates the PI3K/AKT/β-catenin/FOSL1 pathway in an autocrine manner to promote GSC self-renewal and tumor growth. At the same time, POSTN recruits microglia in a paracrine manner and upregulates the expression of CD70 in microglia through the PI3K/AKT/NFκB pathway, thereby promoting the development and function of Treg and generating an immunosuppressive tumor microenvironment. Our findings indicate that targeting the POSTN gene may be a promising approach to ablating GSCs, breaking the immunosuppressive environment and overcoming treatment resistance in GBM.
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