R Script Epichaperomics - Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation

R script associated with manuscript NCOMMS-22-32085A

Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation

Anna Rodina^1,11, Chao Xu^1,11, Chander S. Digwal^1,11, Suhasini Joshi^1,11, Anand R. Santhaseela¹, Sadik Bay¹, Swathi Merugu¹, Aftab Alam¹, Pengrong Yan¹, Chenghua Yang^1,12, Tanaya Roychowdhury¹, Palak Panchal¹, Liza Shrestha¹, Yanlong Kang¹, Sahil Sharma¹, Yogita Patel², Justina Almadovar¹, Adriana Corben^3,13, Mary Alpaugh^1,14, Shanu Modi⁴, Monica L. Guzman⁵, Teng Fei⁶, Tony Taldone¹, Stephen D. Ginsberg^7,8, Hediye Erdjument-Bromage⁹, Thomas A. Neubert⁹, Katia Manova-Todorova¹⁰, Jason C. Young², Meng-Fu Bryan Tsou¹⁰, Tai Wang^1,*, Gabriela Chiosis^1,4,*

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 first-in-class 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.