Leveraging Gα12 signaling to treat glioblastoma

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Abstract Glioblastoma multiforme, one of the most aggressive primary brain tumors, has a dismal prognosis despite treatment advancements in the past decades. Low patient survival is driven by disease recurrency after a period of remission. GBM is a highly invasive tumor, which makes surgical recession difficult. G-protein coupled receptors are increasingly recognized for their ability to regulate tumor growth. Many of these receptors signal through their coupling to the alpha subunit of the heterotrimeric G-protein Ga12. In silico interrogation of GBM in The Cancer Genome Atlas reveals marked upregulation of GNA12, the gene encoding G⍺12, concomitant with overexpression of G-protein coupled receptors (GPCRs) that signal through this G-protein. We recently determined that targeting G⍺12 in human glioma stem cells (GSCs) attenuates tumor cell self-renewal, expression of stem cell genes, and invasion. Concordantly G⍺12 knockdown (KD) reduced invasion of tumors from orthotopically engrafted GSC cells in vivo. Reciprocally, chemogenetic activation of G⍺12 increased invasion. G⍺12 KD tumors assessed by RNA seq showed reduced expression of cell adhesion and migration genes, as well as increased expression of proneural genes. The observed changes in migratory behavior and gene expression suggest that G⍺12 signaling promotes a proneural-to-mesenchymal transition. The evidence that G⍺12 signaling regulates transcriptional programs for stemness and invasion of GSCs identifies this as a potential signaling node for therapeutic intervention. Surgery followed by radiation therapy is the standard of care for GBM. Decreases in stemness and invasiveness, associated with a more proneural state, would be predictive of improved sensitivity to radiation therapy which could in turn ameliorate disease recurrence and damage to healthy brain tissue. Our short-term goal is to provide evidence for enhanced GSC susceptibility to radiation treatment in cells lacking G⍺12 signaling. We will use single dose irradiation of GSCs in cell culture and in tumor bearing mice using image-guided irradiation. Our innovative approach leverages the newly discovered role of G⍺12 on tumor growth and invasiveness to improve GBM treatment. The ability to evaluate radiosensitization, elicited by blockade of G⍺12 signals, in human patient derived glioma cells, using image-guided irradiation is consistent with precision medicine approaches. Thus, our findings could impact radiation treatment of resistant tumors and improve GBM patient survival. If successful, our studies will be the first to demonstrate the benefit of targeting G⍺12 signaling in association with radiation to treat GBM and will implicate G⍺12-coupled receptors and their transcriptionally regulated gene targets as potential points of therapeutic intervention.