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Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
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Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes

Hong Wang1,2,3, Alexander K Diaz3,4, Timothy I Shaw2,5

  • 1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Nature Communications
|August 18, 2019
PubMed

Insights

High-throughput omics revealed key molecular drivers in high-grade glioma (HGG). NTRK1 mutations showed greater oncogenic activity than PDGFRA, highlighting novel therapeutic targets like MYC and JUN.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • High-throughput omics technologies offer powerful tools for understanding complex cancer biology.
  • High-grade glioma (HGG) is an aggressive brain tumor with limited treatment options.

Purpose of the Study:

  • To comprehensively profile the molecular landscape of HGG using multi-omics approaches.
  • To identify master regulators and potential therapeutic vulnerabilities in HGG mouse models driven by RTK oncogenes.

Main Methods:

  • Deep proteome, phosphoproteome, and transcriptome profiling using mass spectrometry.
  • Systems biology analysis to identify master regulators (kinases, transcription factors).
  • CRISPR-Cas9 screening for functional validation of identified targets.

Main Results:

  • Identified 13,860 proteins and 30,431 phosphosites across two HGG models (PDGFRA and NTRK1 driven).
  • NTRK1-driven HGG exhibited higher AKT pathway activation (MYC, JUN) and RTK feedback loops, conferring greater oncogenic potency.
  • 56% of tested master regulators, including TFs (Myc, Jun) and kinases (AMPKa1, AMPKa2), were essential for NTRK-driven HGG cell viability.

Conclusions:

  • Integrative multi-omics analysis successfully identified critical molecular players in HGG.
  • NTRK1 mutations represent a more aggressive HGG subtype with distinct vulnerabilities.
  • Identified master regulators, particularly TFs and metabolic kinases, represent promising therapeutic targets for HGG.

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