@article{a13b0c0df9f14c10ac72a46499b22c72,
title = "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.",
author = "Kwanha Yu and Lin, {Chia Ching John} and Asante Hatcher and Brittney Lozzi and Kathleen Kong and Emmet Huang-Hobbs and Cheng, {Yi Ting} and Beechar, {Vivek B.} and Wenyi Zhu and Yiqun Zhang and Fengju Chen and Mills, {Gordon B.} and Mohila, {Carrie A.} and Creighton, {Chad J.} and Noebels, {Jeffrey L.} and Scott, {Kenneth L.} and Benjamin Deneen",
note = "Funding Information: this endeavour. This work was supported by grants from the Cancer Prevention Research Institute of Texas (RP150334 and RP160192 to B.D., K.L.S., C.A.M. and C.C.), National Cancer Institute-Cancer Therapeutic Discovery (U01-CA217842 to B.D., G.B.M. and K.L.S.), National Institutes of Health (R01-CA223388 to B.D. and J.L.N.; R01-NS071153 to B.D.; T32-HL902332 to K.Y.), the American Cancer Society-Rob Rutherford Glioblastoma Research Postdoctoral Fellowship (PF-15-220-01-TBG to K.Y.), and Howard Hughes Medical Institute Gilliam Fellowship (A.H.). We acknowledge the assistance of the Baylor College of Medicine Mouse Phenotyping Core with funding from the NIH (U54-HG006348). This project was supported by the BCM Small Animal MRI and Texas Children{\textquoteright}s Hospital Small Animal Imaging Facility. Functional Proteomics RPPA Core Facility at MD Anderson Cancer Center, this facility is funded by NCI CA16672. We thank F. F. Lang for providing patient-derived cell lines under the auspices of his Internal Review Board protocol (LAB04-001) post-de-identification.",
year = "2020",
month = feb,
day = "6",
doi = "10.1038/s41586-020-1952-2",
language = "English (US)",
volume = "578",
pages = "166--171",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7793",
}