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Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment1,2. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma3,4. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model ofglioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members ofthe glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment.
In the pursuit of cataloguing the spectrum of somatic mutations for all tumour types, cancer genomics is rapidly approaching a state of saturation mutagenesis5. These crucial advances promise to usher in a new era of personalized medicine, in which patient-specific genomic information is applied in the clinic. One major obstacle in achieving this goal is decoding driver and passenger mutations from these cohorts, as not all mutations affect malignancy, whereas others exert context-specific functions. Mutation 'hotspots' represent variants in key driver genes that occur with high frequency and are found across different types of cancer6. Although widely accepted as the convention for prospective selection of driver mutations, this approach overlooks most mutations and, crucially, does not account for how cellular context influences variant function7-12. Whether related variants exert differential effects on both tumour and microenvironmental phenotypes remains unknown. These limitations illustrate the need for high-throughput, functional and phenotypic screening of individual variant cohorts in contextually appropriate in vivo systems.
Identifying PIK3CA driver variants
The RTK-RAS-PI3K pathway is a key driver of tumorigenesis across all cancers, with 90% ofglioblastoma tumours exhibiting alterations in this pathway13,14. Among the specific genes in this pathway, mutations in the PI3K catalytic subunit PIK3CA are found in 11% ofglioblastoma tumours13. Sequencing...