Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes
| العنوان: | Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes |
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| المؤلفون: | Junmin Peng, Xusheng Wang, Chunliang Li, Bing Bai, Yang Zhang, Suiping Zhou, Haiyan Tan, Jeffrey M. Sifford, Ji-Hoon Cho, Mingming Niu, Yuxin Li, Anthony A. High, Suzanne J. Baker, Hong Wang, Vishwajeeth Pagala, Suresh Thiagarajan, Alexander K. Diaz, Laura D. Hover, Zhiping Wu, Barbara S. Paugh, Abbas Shirinifard, Andras Sablauer, Heather Tillman, Timothy I. Shaw |
| المصدر: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) |
| بيانات النشر: | Nature Publishing Group UK, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Phosphopeptides, Proteomics, Cellular signalling networks, Receptor, Platelet-Derived Growth Factor alpha, Systems biology, Science, Oncogene Protein p65(gag-jun), General Physics and Astronomy, Proteomic analysis, 02 engineering and technology, PDGFRA, Computational biology, Biology, AMP-Activated Protein Kinases, General Biochemistry, Genetics and Molecular Biology, Receptor tyrosine kinase, Article, Transcriptome, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Mice, Animals, Receptor, trkA, lcsh:Science, Transcription factor, Feedback, Physiological, Multidisciplinary, Brain Neoplasms, Gene Expression Profiling, Systems Biology, General Chemistry, Oncogenes, Glioma, 021001 nanoscience & nanotechnology, Phosphoproteins, Up-Regulation, Gene expression profiling, Disease Models, Animal, 030104 developmental biology, Proteome, Mutation, biology.protein, lcsh:Q, 0210 nano-technology, Proto-Oncogene Proteins c-akt, Signal Transduction |
| الوصف: | 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. Multi-omic profiling is a powerful approach to dissecting molecular mechanisms in disease. Here the authors generate whole proteome, phosphoproteome and transcriptome profiles from two mouse models of high-grade glioma driven by different oncogenes, and validate identified master regulators with a CRISPR screen. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b7b5b7341899c63b0abe6d5badd10f36 http://europepmc.org/articles/PMC6697699 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....b7b5b7341899c63b0abe6d5badd10f36 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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