OPINION

Adapting to stress — chaperome networks in cancer

Abstract

In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.

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Fig. 1: Chaperome connectivity from normal cellular states to conditions characterized by increasing stress.
Fig. 2: Functional gains from formation of multimeric chaperome scaffolding platforms under cellular stress.
Fig. 3: Chaperome networks use redundancy to protect from temporary or partial impairment.

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Acknowledgements

G.C. is supported by the US National Institutes of Health (NIH) (R01 CA172546, R01 CA155226, P01 CA186866, P30 CA08748 and P50 CA192937), the Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center of the Memorial Sloan Kettering Cancer Center; T.W. is supported by the Lymphoma Research Foundation; T.L.S.A. is supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (17/01130-6); and J.L.B. is supported by the Cystic Fibrosis Foundation Therapeutics (BRODSK13XX0) and by the NIH (grants GM75061 and DK79307).

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Nature Reviews Cancer thanks R. Kaufman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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S.J., T.W., T.L.S.A. and S.S. researched data for the article and contributed to the writing of the article and to the review of the manuscript. T.W., T.L.S.A. and G.C. designed the figures and their content. J.L.B. edited the manuscript and provided specific text. G.C. designed the content of the manuscript, researched data for the article and wrote, edited and reviewed the manuscript.

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Correspondence to Gabriela Chiosis.

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G.C. has partial ownership in Samus Therapeutics Inc., which develops chaperome inhibitors. S.J., T.W., T.L.S.A., S.S. and J.L.B. declare no competing interests.

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Joshi, S., Wang, T., Araujo, T.L.S. et al. Adapting to stress — chaperome networks in cancer. Nat Rev Cancer 18, 562–575 (2018). https://doi.org/10.1038/s41568-018-0020-9

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