Multi-scale signaling and tumor evolution in high-grade gliomas
Jingxian Liu, Song Cao, Kathleen J. Imbach, Marina A. Gritsenko, T. Mamie Lih, Jennifer Kyle, Tomer M. Yaron-Barir, Zev A. Binder, Yize Li, Ilya Strunilin, Yi-Ting Wang, Chia‐Feng Tsai, Weiping Ma, Lijun Chen, Natalie M. Clark, Andrew Shinkle, Nataly Naser Al Deen, Wagma Caravan, Andrew Houston, Faria Anjum Simin, Matthew A. Wyczalkowski, Liang-Bo Wang, Erik Storrs, Siqi Chen, Ritvik Illindala, Yuping D. Li, Reyka G. Jayasinghe, Dmitry Rykunov, Sandra Cottingham, Rosalie Chu, Karl Weitz, Ronald Moore, Tyler J. Sagendorf, Vladislav Petyuk, Michael Nestor, Lisa Bramer, Kelly G. Stratton, Athena Schepmoes, Sneha Couvillion, Josie Eder, Young‐Mo Kim, Yuqian Gao, Thomas Fillmore, Rui Zhao, Matthew Monroe, Austin N. Southard-Smith, Yang Eric Li, Rita Jui-Hsien Lu, Jared L. Johnson, Maciej Wiznerowicz, Galen Hostetter, Chelsea J. Newton, Karen A. Ketchum, Ratna R. Thangudu, Jill S. Barnholtz‐Sloan, Pei Wang, David Fenyö, Eunkyung An, Mathangi Thiagarajan, Ana I. Robles, D.R. Mani, Richard D. Smith, Eduard Porta‐Pardo, Lewis C. Cantley, Antonio Iavarone, Feng Chen, Mehdi Mesri, MacLean P. Nasrallah, Hui Zhang, Adam Resnick, Milan G. Chheda, Karin Rodland, Tao Liu, Li Ding, Anupriya Agarwal, Iyad Alnahhas, Mitual Amin, Eunkyung An, Matthew L. Anderson, David W. Andrews, Meenakshi Anurag, Jill S. Barnholtz-Sloan, Thomas Bauer, Jasmin Bavarva, Zev A. Binder, Michael J. Birrer, Uma Borate, Melissa Borucki, Lisa M. Bramer, Steven Brem, Shuang Cai, Lewis C. Cantley, Song Cao, Wagma Caravan, Steven A Carr, Daniel W. Chan, Lijun Chen, Lin S. Chen, Xi S. Chen, David Chesla
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.