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PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.

ABSTRACT: 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 of glioblastoma, 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 of the 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.

SUBMITTER: Yu K

PROVIDER: S-EPMC7577741 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.

Yu Kwanha K Lin Chia-Ching John CJ Hatcher Asante A Lozzi Brittney B Kong Kathleen K Huang-Hobbs Emmet E Cheng Yi-Ting YT Beechar Vivek B VB Zhu Wenyi W Zhang Yiqun Y Chen Fengju F Mills Gordon B GB Mohila Carrie A CA Creighton Chad J CJ Noebels Jeffrey L JL Scott Kenneth L KL Deneen Benjamin B

Nature 20200129 7793

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 microenvironment<sup>1,2</sup>. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma<sup>3,4</sup>. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tu ...[more]

PMID: 31996845

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Project description:Human cancer is caused by the accumulation of genetic alterations in cells. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and thus represent promising targets for therapeutic intervention. We have previously described a computational approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to determine the temporal sequence of genetic alterations during tumorigenesis from cross-sectional genomic data of tumors at their fully transformed stage. Since alterations within a set of genes belonging to a particular signaling pathway may have similar or equivalent effects, we applied a pathway-based systems biology approach to the RESIC methodology. This method was used to determine whether alterations of specific pathways develop early or late during malignant transformation. When applied to primary glioblastoma (GBM) copy number data from The Cancer Genome Atlas (TCGA) project, RESIC identified a temporal order of pathway alterations consistent with the order of events in secondary GBMs. We then further subdivided the samples into the four main GBM subtypes and determined the relative contributions of each subtype to the overall results: we found that the overall ordering applied for the proneural subtype but differed for mesenchymal samples. The temporal sequence of events could not be identified for neural and classical subtypes, possibly due to a limited number of samples. Moreover, for samples of the proneural subtype, we detected two distinct temporal sequences of events: (i) RAS pathway activation was followed by TP53 inactivation and finally PI3K2 activation, and (ii) RAS activation preceded only AKT activation. This extension of the RESIC methodology provides an evolutionary mathematical approach to identify the temporal sequence of pathway changes driving tumorigenesis and may be useful in guiding the understanding of signaling rearrangements in cancer development.

Dataset Information

PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.

Publications

PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.

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