PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.

Autor: Yu K; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Lin CJ; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Hatcher A; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Lozzi B; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Kong K; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Huang-Hobbs E; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Cheng YT; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Beechar VB; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Zhu W; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA., Zhang Y; Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA., Chen F; Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA., Mills GB; Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health Science University, Portland, OR, USA., Mohila CA; Department of Pathology, Texas Children's Hospital, Houston, TX, USA., Creighton CJ; Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.; Department of Medicine, Baylor College of Medicine, Houston, TX, USA., Noebels JL; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.; Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX, USA.; Department of Neurology, Baylor College of Medicine, Houston, TX, USA., Scott KL; Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX, USA., Deneen B; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. deneen@bcm.edu.; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. deneen@bcm.edu.; Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA. deneen@bcm.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Feb; Vol. 578 (7793), pp. 166-171. Date of Electronic Publication: 2020 Jan 29.
DOI: 10.1038/s41586-020-1952-2
Abstrakt: 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 1,2 . Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma 3,4 . 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.
Databáze: MEDLINE
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