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 () and Gabriela Chiosis ()
Additional contact information
Anna Rodina: Memorial Sloan Kettering Cancer Center
Chao Xu: Memorial Sloan Kettering Cancer Center
Chander S. Digwal: Memorial Sloan Kettering Cancer Center
Suhasini Joshi: Memorial Sloan Kettering Cancer Center
Yogita Patel: McGill University
Anand R. Santhaseela: Memorial Sloan Kettering Cancer Center
Sadik Bay: Memorial Sloan Kettering Cancer Center
Swathi Merugu: Memorial Sloan Kettering Cancer Center
Aftab Alam: Memorial Sloan Kettering Cancer Center
Pengrong Yan: Memorial Sloan Kettering Cancer Center
Chenghua Yang: Memorial Sloan Kettering Cancer Center
Tanaya Roychowdhury: Memorial Sloan Kettering Cancer Center
Palak Panchal: Memorial Sloan Kettering Cancer Center
Liza Shrestha: Memorial Sloan Kettering Cancer Center
Yanlong Kang: Memorial Sloan Kettering Cancer Center
Sahil Sharma: Memorial Sloan Kettering Cancer Center
Justina Almodovar: Memorial Sloan Kettering Cancer Center
Adriana Corben: Memorial Sloan Kettering Cancer Center
Mary L. Alpaugh: Memorial Sloan Kettering Cancer Center
Shanu Modi: Memorial Sloan Kettering Cancer Center
Monica L. Guzman: Division of Hematology Oncology, Weill Cornell Medicine
Teng Fei: Memorial Sloan Kettering Cancer Center
Tony Taldone: Memorial Sloan Kettering Cancer Center
Stephen D. Ginsberg: NYU Grossman School of Medicine
Hediye Erdjument-Bromage: NYU Grossman School of Medicine
Thomas A. Neubert: 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: McGill University
Tai Wang: Memorial Sloan Kettering Cancer Center
Gabriela Chiosis: Memorial Sloan Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-39241-7

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