TRPM7 induces tumorigenesis and stemness through Notch activation in glioma

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The current standard of care of surgery and radiochemotherapy for glioblastomas (GBM) is inadequate and has not resulted in improved prognosis. Accumulating evidences show that the failure of using current chemo (temozolomide, TMZ)- and radio- therapies to treat GBM and the resultant high tumor recurrence are attributed to the presence of a small subpopulation of glioma stem cells (GSC), which is characterized by their stem cell- like properties and aggressive behavior. Under hypoxic conditions, GSC increase the activation of several Notch genes, which hold a prognostic implication, as upregulated Notch genes are associated with poor survival. Notch signaling is highly active in GSC, inhibits differentiation, maintains stem-like properties, and, therefore, is responsible for GBM tumorigenesis and stemness. Our project highlights transient receptor potential melastatin- related-7 (TRPM7)’s role in Notch signaling and glioma treatment failure. TRPM7 encodes a Ca2+ permeable nonselective cation channel fused with a serine/threonine kinase at its carboxyl terminus. Our group found that the suppression of TRPM7 channels inhibits proliferation, migration, and invasion of malignant human gliomas, indicating that TRPM7 channels may represent a novel and promising target for therapeutic intervention of malignant glioma. Furthermore, the effect of TRPM7 on the proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate GSC growth and proliferation through STAT3 and Notch signaling pathways. In addition, the preliminary data in this proposal show that decreased expression of TRPM7 is correlated with decreased active Notch1 intracellular domain (NICD) from the Notch1 receptor and reduced GSC marker CD133 expression in the glioma cell lines/xenoline tested. Our results indicate that TRPM7 regulates the Notch pathway in most glioma cell lines/xenoline despite the high heterogeneity and variations in glioma’s biological characteristics. In this proposal, we hypothesize that TRPM7 molecular pathway is functionally connected to Notch-induced stemness, and TRPM7 may be a novel GBM drug target. In this project, we will utilize patient-derived xenolines (PDX) that closely mimics the biological and physiological features of in vivo real cells and tissues to test our hypothesis. Aim 1: Determine the role of TRPM7 in the regulation of Ca2+ and Mg2+ homeostasis in GBM PDX and PDX- GSC. Aim 2: Determine the role of the Notch signaling pathway regulated by TRPM7 in the progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using PDX and PDX-GSC. Aim 3: Investigate whether targeting TRPM7 reduces tumor growth in mouse PDX glioma models and sensitizes tumor to TMZ- mediated apoptosis. Accomplishing this study will delineate the molecular mechanisms of TRPM7 in the development and progression of glioma tumorigenesis and stemness, as well as develop TRPM7 as a novel drug target for glioma patients.