PIK3CA Mutations Induce Neuronal Hyperactivity during Glioma Formation

Based on the fact that the RTK–RAS–PI3K pathway is dysfunctional in 90% of glioblastomas, Yu, Lin, and colleagues used a native mouse model of glioblastoma to perform high-throughput in vivo screening for PIC3KA mutations that drive glioma formation. This screen identified previously known hotspot mutations as well as new potential driver mutations, each of which accelerated glioma formation to a different extent. Further, as RNA-sequencing (RNA-seq) experiments revealed, the variants may even have promoted glioma formation via distinct molecular mechanisms. Serial video electroencephalography experiments showed that the presence of either of two putative driver mutations in PIC3KA identified in the screen (C420R and H1047R) in tumors promoted network hyperexcitability at early stages of tumor progression. Examination of the tumor microenvironments (TME) of PIC3KA^C420R- and PIC3KA^H1047R-driven tumors revealed that there were more excitatory synapses and fewer inhibitory synapses at the peritumoral margins than in the TME of tumors driven by a PIC3KA mutation not associated with hyperexcitability. The findings regarding hyperexcitability and synaptic alterations in the TME were confirmed using patient-derived xenograft models in which mice were transplanted with glioma stem-cell lines overexpressing each PIC3KA variant. Despite the aforementioned similarities between PIC3KA^C420R- and PIC3KA^H1047R-driven tumors, further experiments revealed that the H1047R mutation induced neuronal hyperexcitability on its own in a nontumor context, whereas the C420R mutation did so only in glial tumors, implying differences in the underlying mechanisms. Deeper analysis of the RNA-seq data suggested that glypican 3 (GPC3) contributed to the non–cell autonomous mechanism by which the C420R mutation promoted tumorigenesis and the observed synaptic abnormalities. Indeed, mice bearing Gpc3-knockout tumors harboring PIC3KA^C420R had extended survival compared with PIC3KA^C420R-mutant tumors with wild-type Gpc3, and tumors overexpressing Gpc3 exhibited earlier-onset neuronal hyperexcitability and caused convulsive seizures at earlier stages. Combined with recent findings that increased neuronal activity promotes glioma proliferation, these results support the role of a positive feedback mechanism wherein gliomas induce neuronal hyperactivity and that hyperactivity promotes glioma growth.

Yu K, Lin CJ, Hatcher A, Lozzi B, Kong K, Huang-Hobbs E, et al. PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature 2020;578:166–71.

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