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PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis

Author

Listed:
  • 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
    Baylor College of Medicine)

  • Jeffrey L. Noebels

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Kenneth L. Scott

    (Baylor College of Medicine)

  • Benjamin Deneen

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

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.

Suggested Citation

  • 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 & Car, 2020. "PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis," Nature, Nature, vol. 578(7793), pages 166-171, February.
    • Handle: RePEc:nat:nature:v:578:y:2020:i:7793:d:10.1038_s41586-020-1952-2
    DOI: 10.1038/s41586-020-1952-2
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    Cited by:

    1. Jochen Meyer & Kwanha Yu & Estefania Luna-Figueroa & Benjamin Deneen & Jeffrey Noebels, 2024. "Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Corina Anastasaki & Juan Mo & Ji-Kang Chen & Jit Chatterjee & Yuan Pan & Suzanne M. Scheaffer & Olivia Cobb & Michelle Monje & Lu Q. Le & David H. Gutmann, 2022. "Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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