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Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes

Author

Listed:
  • Hong Wang

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    University of Tennessee Health Science Center)

  • Alexander K. Diaz

    (University of Tennessee Health Science Center
    St. Jude Children’s Research Hospital)

  • Timothy I. Shaw

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Yuxin Li

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Mingming Niu

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Ji-Hoon Cho

    (St. Jude Children’s Research Hospital)

  • Barbara S. Paugh

    (St. Jude Children’s Research Hospital)

  • Yang Zhang

    (St. Jude Children’s Research Hospital)

  • Jeffrey Sifford

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Bing Bai

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    Nanjing University Medical School)

  • Zhiping Wu

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Haiyan Tan

    (St. Jude Children’s Research Hospital)

  • Suiping Zhou

    (St. Jude Children’s Research Hospital)

  • Laura D. Hover

    (St. Jude Children’s Research Hospital)

  • Heather S. Tillman

    (St. Jude Children’s Research Hospital)

  • Abbas Shirinifard

    (St. Jude Children’s Research Hospital)

  • Suresh Thiagarajan

    (St. Jude Children’s Research Hospital)

  • Andras Sablauer

    (St. Jude Children’s Research Hospital)

  • Vishwajeeth Pagala

    (St. Jude Children’s Research Hospital)

  • Anthony A. High

    (St. Jude Children’s Research Hospital)

  • Xusheng Wang

    (St. Jude Children’s Research Hospital)

  • Chunliang Li

    (St. Jude Children’s Research Hospital)

  • Suzanne J. Baker

    (St. Jude Children’s Research Hospital)

  • Junmin Peng

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

Abstract

High throughput omics approaches provide an unprecedented opportunity for dissecting molecular mechanisms in cancer biology. Here we present deep profiling of whole proteome, phosphoproteome and transcriptome in two high-grade glioma (HGG) mouse models driven by mutated RTK oncogenes, PDGFRA and NTRK1, analyzing 13,860 proteins and 30,431 phosphosites by mass spectrometry. Systems biology approaches identify numerous master regulators, including 41 kinases and 23 transcription factors. Pathway activity computation and mouse survival indicate the NTRK1 mutation induces a higher activation of AKT downstream targets including MYC and JUN, drives a positive feedback loop to up-regulate multiple other RTKs, and confers higher oncogenic potency than the PDGFRA mutation. A mini-gRNA library CRISPR-Cas9 validation screening shows 56% of tested master regulators are important for the viability of NTRK-driven HGG cells, including TFs (Myc and Jun) and metabolic kinases (AMPKa1 and AMPKa2), confirming the validity of the multiomics integrative approaches, and providing novel tumor vulnerabilities.

Suggested Citation

  • Hong Wang & Alexander K. Diaz & Timothy I. Shaw & Yuxin Li & Mingming Niu & Ji-Hoon Cho & Barbara S. Paugh & Yang Zhang & Jeffrey Sifford & Bing Bai & Zhiping Wu & Haiyan Tan & Suiping Zhou & Laura D., 2019. "Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11661-4
    DOI: 10.1038/s41467-019-11661-4
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