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

Author

Listed:
  • 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
    Second Military Medical University)

  • 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
    Maimonides Medical Center)

  • Mary L. Alpaugh

    (Memorial Sloan Kettering Cancer Center
    Rowan University)

  • 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
    Nathan Kline Institute)

  • 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
    Memorial Sloan Kettering Cancer Center)

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.

Suggested Citation

  • 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 P, 2023. "Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation," Nature Communications, Nature, vol. 14(1), pages 1-26, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39241-7
    DOI: 10.1038/s41467-023-39241-7
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    References listed on IDEAS

    as
    1. Laura Bonetta, 2010. "Interactome under construction," Nature, Nature, vol. 468(7325), pages 851-852, December.
    2. Maria Carmen Inda & Suhasini Joshi & Tai Wang & Alexander Bolaender & Srinivasa Gandu & John Koren III & Alicia Yue Che & Tony Taldone & Pengrong Yan & Weilin Sun & Mohammad Uddin & Palak Panchal & Ma, 2020. "The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    3. Keriann M. Backus & Bruno E. Correia & Kenneth M. Lum & Stefano Forli & Benjamin D. Horning & Gonzalo E. González-Páez & Sandip Chatterjee & Bryan R. Lanning & John R. Teijaro & Arthur J. Olson & Denn, 2016. "Proteome-wide covalent ligand discovery in native biological systems," Nature, Nature, vol. 534(7608), pages 570-574, June.
    4. Mengjie Sun & Mingkang Jia & He Ren & Biying Yang & Wangfei Chi & Guangwei Xin & Qing Jiang & Chuanmao Zhang, 2021. "NuMA regulates mitotic spindle assembly, structural dynamics and function via phase separation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    5. Anna Rodina & Tai Wang & Pengrong Yan & Erica DaGama Gomes & Mark P. S. Dunphy & Nagavarakishore Pillarsetty & John Koren & John F. Gerecitano & Tony Taldone & Hongliang Zong & Eloisi Caldas-Lopes & M, 2016. "The epichaperome is an integrated chaperome network that facilitates tumour survival," Nature, Nature, vol. 538(7625), pages 397-401, October.
    6. Alexander Bolaender & Danuta Zatorska & Huazhong He & Suhasini Joshi & Sahil Sharma & Chander S. Digwal & Hardik J. Patel & Weilin Sun & Brandon S. Imber & Stefan O. Ochiana & Maulik R. Patel & Liza S, 2021. "Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
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    Cited by:

    1. Mark R. Woodford & Dimitra Bourboulia & Mehdi Mollapour, 2023. "Epichaperomics reveals dysfunctional chaperone protein networks," Nature Communications, Nature, vol. 14(1), pages 1-3, December.
    2. Tanaya Roychowdhury & Seth W. McNutt & Chiranjeevi Pasala & Hieu T. Nguyen & Daniel T. Thornton & Sahil Sharma & Luke Botticelli & Chander S. Digwal & Suhasini Joshi & Nan Yang & Palak Panchal & Soupa, 2024. "Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation," Nature Communications, Nature, vol. 15(1), pages 1-28, December.

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