Nature Communications (Jun 2023)
Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation
- Anna Rodina,
- Chao Xu,
- Chander S. Digwal,
- Suhasini Joshi,
- Yogita Patel,
- Anand R. Santhaseela,
- Sadik Bay,
- Swathi Merugu,
- Aftab Alam,
- Pengrong Yan,
- Chenghua Yang,
- Tanaya Roychowdhury,
- Palak Panchal,
- Liza Shrestha,
- Yanlong Kang,
- Sahil Sharma,
- Justina Almodovar,
- Adriana Corben,
- Mary L. Alpaugh,
- Shanu Modi,
- Monica L. Guzman,
- Teng Fei,
- Tony Taldone,
- Stephen D. Ginsberg,
- Hediye Erdjument-Bromage,
- Thomas A. Neubert,
- Katia Manova-Todorova,
- Meng-Fu Bryan Tsou,
- Jason C. Young,
- Tai Wang,
- Gabriela Chiosis
Affiliations
- Anna Rodina
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Chao Xu
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Chander S. Digwal
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Suhasini Joshi
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Yogita Patel
- Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, McGill University
- Anand R. Santhaseela
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Sadik Bay
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Swathi Merugu
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Aftab Alam
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Pengrong Yan
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Chenghua Yang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Tanaya Roychowdhury
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Palak Panchal
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Liza Shrestha
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Yanlong Kang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Sahil Sharma
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Justina Almodovar
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Adriana Corben
- Department of Pathology, Memorial Sloan Kettering Cancer Center
- Mary L. Alpaugh
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Shanu Modi
- Department of Medicine, Division of Solid Tumors, Memorial Sloan Kettering Cancer Center
- Monica L. Guzman
- Department of Medicine, Division of Hematology Oncology, Weill Cornell Medicine
- Teng Fei
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center
- Tony Taldone
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Stephen D. Ginsberg
- Departments of Psychiatry, Neuroscience & Physiology & the NYU Neuroscience Institute, NYU Grossman School of Medicine
- Hediye Erdjument-Bromage
- Department of Neuroscience and Physiology and Neuroscience Institute, NYU Grossman School of Medicine
- Thomas A. Neubert
- Department of Neuroscience and Physiology and Neuroscience Institute, NYU Grossman School of Medicine
- Katia Manova-Todorova
- Cell Biology Program, Memorial Sloan Kettering Cancer Center
- Meng-Fu Bryan Tsou
- Cell Biology Program, Memorial Sloan Kettering Cancer Center
- Jason C. Young
- Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, McGill University
- Tai Wang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- Gabriela Chiosis
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center
- DOI
- https://doi.org/10.1038/s41467-023-39241-7
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 26
Abstract
Abstract Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based ‘omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.