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

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. Hover, Heather S. Tillman, Abbas Shirinifard, Suresh Thiagarajan, Andras Sablauer, Vishwajeeth Pagala, Anthony A. High, Xusheng Wang, Chunliang Li, Suzanne J. Baker () and Junmin Peng ()
Additional contact information
Hong Wang: St. Jude Children’s Research Hospital
Alexander K. Diaz: University of Tennessee Health Science Center
Timothy I. Shaw: St. Jude Children’s Research Hospital
Yuxin Li: St. Jude Children’s Research Hospital
Mingming Niu: 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
Bing Bai: St. Jude Children’s Research Hospital
Zhiping Wu: 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

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11661-4

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