PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis

Kwanha Yu, Chia Ching John Lin, Asante Hatcher, Brittney Lozzi, Kathleen Kong, Emmet Huang-Hobbs, Yi Ting Cheng, Vivek B. Beechar, Wenyi Zhu, Yiqun Zhang, Fengju Chen, Gordon B. Mills, Carrie A. Mohila, Chad J. Creighton, Jeffrey L. Noebels, Kenneth L. Scott, Benjamin Deneen

    Research output: Contribution to journalArticle

    7 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)166-171
    Number of pages6
    JournalNature
    Volume578
    Issue number7793
    DOIs
    StatePublished - Feb 6 2020

    ASJC Scopus subject areas

    • General

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    Yu, K., Lin, C. C. J., Hatcher, A., Lozzi, B., Kong, K., Huang-Hobbs, E., Cheng, Y. T., Beechar, V. B., Zhu, W., Zhang, Y., Chen, F., Mills, G. B., Mohila, C. A., Creighton, C. J., Noebels, J. L., Scott, K. L., & Deneen, B. (2020). PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature, 578(7793), 166-171. https://doi.org/10.1038/s41586-020-1952-2