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 and Benjamin Deneen ()
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Kwanha Yu: Baylor College of Medicine
Chia-Ching John Lin: Baylor College of Medicine
Asante Hatcher: Baylor College of Medicine
Brittney Lozzi: Baylor College of Medicine
Kathleen Kong: Baylor College of Medicine
Emmet Huang-Hobbs: Baylor College of Medicine
Yi-Ting Cheng: Baylor College of Medicine
Vivek B. Beechar: Baylor College of Medicine
Wenyi Zhu: Baylor College of Medicine
Yiqun Zhang: Division of Biostatistics, Baylor College of Medicine
Fengju Chen: Division of Biostatistics, Baylor College of Medicine
Gordon B. Mills: Knight Cancer Institute, Oregon Health Science University
Carrie A. Mohila: Texas Children’s Hospital
Chad J. Creighton: Division of Biostatistics, Baylor College of Medicine
Jeffrey L. Noebels: Baylor College of Medicine
Kenneth L. Scott: Baylor College of Medicine
Benjamin Deneen: Baylor College of Medicine

Nature, 2020, vol. 578, issue 7793, 166-171

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-1952-2

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