Protein-protein interaction networks in disease

Protein-protein interaction networks in disease


Understanding adaptive responses to stressors and how these differ between normal and diseased tissues remains unsatisfactorily addressed. A key to addressing this unresolved biological question is to study how stressors impact tissue-specific ’interactomes’, the intricate proteomewide cellular networks of proteins linked through interactions. In this context interactomes are maps of how stressors, including genetic lesions, proteotoxic and environmental insults, individually or combined, alter protein-protein interaction (PPI) networks and perturb the system as a whole.

Our program takes advantage of properties of protein-protein interaction networks (i.e. interactome networks) to understand, diagnose and treat diseases, such as cancer and neurodegenerative diseases.

It aims to investigate the identity and the architecture of interactome networks in cells exposed to chronic molecular and environmental stressors with the goal of understanding disease mechanisms and identifying vulnerabilities.

It aims to take advantage of these vulnerabilities to discover and develop drug candidates, biomarkers, diagnostics and treatment strategies.

Our ultimate goal is the translation of our discoveries from bench to bedside.

protein networks

Rodina A, Xu C, Digwal CS, Joshi S, Patel Y, Santhaseela AR, Bay S, Merugu S, Alam A, Yan P, Yang C, Roychowdhury T, Panchal P, Shrestha L, Kang Y, Sharma S, Almodovar J, Corben A, Alpaugh ML, Modi S, Guzman ML, Fei T, Taldone T, Ginsberg SD, Erdjument-Bromage H, Neubert TA, Manova-Todorova K, Tsou MB, Young JC, Wang T, Chiosis G. Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation. Nat Commun. 2023;14(1):3742. doi: 10.1038/s41467-023-39241-7.

Ginsberg SD, Sharma S, Norton L, Chiosis G. Targeting stressor-induced dysfunctions in protein-protein interaction networks via epichaperomes. Trends Pharmacol Sci. 2023;44(1):20-33. doi: 10.1016/ 

Joshi S, Gomes ED, Wang T, Corben A, Taldone T, Gandu S, Xu C, Sharma S, Buddaseth S, Yan P, Chan LYL, Gokce A, Rajasekhar VK, Shrestha L, Panchal P, Almodovar J, Digwal CS, Rodina A, Merugu S, Pillarsetty N, Miclea V, Peter RI, Wang W, Ginsberg SD, Tang L, Mattar M, de Stanchina E, Yu KH, Lowery M, Grbovic-Huezo O, O’Reilly EM, Janjigian Y, Healey JH, Jarnagin WR, Allen PJ, Sander C, Erdjument-Bromage H, Neubert TA, Leach SD, Chiosis G. Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer. Commun Biol. 2021 Nov 25;4(1):1333. doi: 10.1038/s42003-021-02842-3.

Inda MC, Joshi S, Wang T, Bolaender A, Gandu S, Koren III J, Che AY, Taldone T, Yan P, Sun W, Uddin M, Panchal P, Riolo M, Shah S, Barlas A, Xu K, Chan LYL, Gruzinova A, Kishinevsky S, Studer L,Fossati V, Noggle SA, White JR, de Stanchina E, Sequeira S, Anthoney KH, Steele JW, Manova-Todorova K,Patil S, Dunphy MP, Pillarsetty N, Pereira AC, Erdjument-Bromage H, Neubert TA, Rodina A, Ginsberg SD, De Marco Garcia N, Luo W, Chiosis G. The epichaperome is a propagator of toxic hippocampal stress and leads to protein connectivity-based dysfunction. Nature Commun. 2020 Jan 16;11(1):319.

Pillarsetty N, Jhaveri K, Taldone T, Caldas-Lopes E, Punzalan B, Joshi S, Bolaender A, Uddin MM, Rodina A, Yan P, Ku A, Ku T, Shah SK, Lyashchenko S, Burnazi E, Wang T, Lecomte N, Janjigian Y, Younes A, Batlevi CW, Guzman ML, Roboz GJ, Koziorowski J, Zanzonico P, Alpaugh ML, Corben A, Modi S, Norton L, Larson SM, Lewis JS, Chiosis G*, Gerecitano JF, Dunphy MPS. (*lead contact) Paradigms for Precision Medicine in Epichaperome Cancer Therapy. Cancer Cell. 2019 Nov 11;36(5):559-573.e7. doi: 10.1016/j.ccell.2019.09.007. Epub 2019 Oct 24.

Joshi S, Wang T, Araujo TLS, Sharma S, Brodsky JL, Chiosis G. Adapting to stress - chaperome networks in cancer. Nat Rev Cancer. 2018;18(9):562-75. PMCID: PMC6108944. Altmetric 352. PubMed

  • Featured on NBC, ABC, Fox, PR newswire etc, Altmetric 362

Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature. 2016;538(7625):397-401. PMCID: PMC5283383. Altmetric 439. PubMed

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Kishinevsky S, Wang T, Rodina A, Chung SY, Xu C, Philip J, Taldone T, Joshi S, Alpaugh ML, Bolaender A, Gutbier S, Sandhu D, Fattahi F, Zimmer B, Shah SK, Chang E, Inda C, Koren J, Saurat NG, Leist M, Gross SS, Seshan VE, Klein C, Tomishima MJ, Erdjument-Bromage H, Neubert TA, Henrickson RC, Chiosis G, Studer L. HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nature Communications. 2018;9(1):4345.