1. Multi-scale signaling and tumor evolution in high-grade gliomas.
- Author
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Liu J, Cao S, Imbach KJ, Gritsenko MA, Lih TM, Kyle JE, Yaron-Barir TM, Binder ZA, Li Y, Strunilin I, Wang YT, Tsai CF, Ma W, Chen L, Clark NM, Shinkle A, Naser Al Deen N, Caravan W, Houston A, Simin FA, Wyczalkowski MA, Wang LB, Storrs E, Chen S, Illindala R, Li YD, Jayasinghe RG, Rykunov D, Cottingham SL, Chu RK, Weitz KK, Moore RJ, Sagendorf T, Petyuk VA, Nestor M, Bramer LM, Stratton KG, Schepmoes AA, Couvillion SP, Eder J, Kim YM, Gao Y, Fillmore TL, Zhao R, Monroe ME, Southard-Smith AN, Li YE, Jui-Hsien Lu R, Johnson JL, Wiznerowicz M, Hostetter G, Newton CJ, Ketchum KA, Thangudu RR, Barnholtz-Sloan JS, Wang P, Fenyö D, An E, Thiagarajan M, Robles AI, Mani DR, Smith RD, Porta-Pardo E, Cantley LC, Iavarone A, Chen F, Mesri M, Nasrallah MP, Zhang H, Resnick AC, Chheda MG, Rodland KD, Liu T, and Ding L
- Subjects
- Humans, Mutation, Proteomics methods, Protein Processing, Post-Translational, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma pathology, Glioblastoma metabolism, Phosphorylation, Neoplasm Grading, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms metabolism, Signal Transduction, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Glioma genetics, Glioma pathology, Glioma metabolism
- Abstract
Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas., Competing Interests: Declaration of interests T.M.Y. is a co-founder, stockholder, and member of the board of directors of DESTROKE, Inc., an early stage start-up developing mobile technology for automated clinical stroke detection. J.L.J. has received consulting fees from Scorpion Therapeutics and Volastra Therapeutics. L.C.C. is a founder and member of the board of directors of Agios Pharmaceuticals and is a founder of Petra Pharmaceuticals. L.C.C. is an inventor on patents (pending) for Combination Therapy for PI3K-associated Disease or Disorder, and The Identification of Therapeutic Interventions to Improve Response to PI3K Inhibitors for Cancer Treatment. L.C.C. is a co-founder and shareholder in Faeth Therapeutics. P.W. is a statistical consultant for Sema4. M.G.C. receives research support from Merck, Orbus Therapeutics, and NeoimmuneTech Inc, and royalties from UpToDate., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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