Multi-scale signaling and tumor evolution in high-grade gliomas.

in Cancer cell by Jingxian Liu, Song Cao, Kathleen J Imbach, Marina A Gritsenko, Tung-Shing M Lih, Jennifer E 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 L Cottingham, Rosalie K Chu, Karl K Weitz, Ronald J Moore, Tyler Sagendorf, Vladislav A Petyuk, Michael Nestor, Lisa M Bramer, Kelly G Stratton, Athena A Schepmoes, Sneha P Couvillion, Josie Eder, Young-Mo Kim, Yuqian Gao, Thomas L Fillmore, Rui Zhao, Matthew E Monroe, Austin N Southard-Smith, Yang E 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 C Resnick, Milan G Chheda, Karin D Rodland, Tao Liu, Li Ding, ,

TLDR

  • The study is trying to understand the different ways that cancer cells in the brain grow and change. They did this by looking at many different types of data, like genetic information, protein information, and metabolic information. They found that there are many different changes happening in the cells that are related to each other, and that these changes are important for the cancer to keep growing. They also found that a specific protein called PTPN11 is very important for these changes to happen.

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.

Overview

  • The study aims to expand the molecular landscape of high-grade glioma 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. The study applies 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. The primary objective of the study is to identify 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.

Comparative Analysis & Findings

  • The study identifies 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.

Implications and Future Directions

  • The study's findings provide a comprehensive understanding of the molecular landscape of high-grade glioma and identify potential therapeutic targets for the treatment of this deadly brain cancer. Future research should focus on developing targeted therapies based on the identified molecular alterations and validating their efficacy in preclinical and clinical studies. Additionally, the study highlights the importance of integrating multiple omics data types to gain a more comprehensive understanding of the complex regulatory interactions governing tumor development and evolution.
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