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Connecting copper and cancer: from transition metal signalling to metalloplasia

Abstract

Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.

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Fig. 1: Overview of systemic and cellular copper homeostasis.
Fig. 2: Copper metalloallostery and signalling promotes cell growth/proliferation and autophagy pathways.
Fig. 3: Therapeutic strategies to target cuproplasia in cancer.

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Acknowledgements

The authors thank the following sources for funding: NIH (GM79465 and GM139245 to C.J.C., GM124749 to D.C.B., R01-GM084176 to K.J.F., GM120211 to P.A.C., GM111672 to V.M.G., R21-GM129592 to M.R., R01-NS109307 to P.Y., CA190265 and DK116859 to M.J.P., Z01 HD008768 and Z01 HD008892 to S.G.K., CA53840 and DK124907 to N.K.T. and R01-GM101502, R01-DK117396 and R01-DK071865 to S.L.), the US National Cancer Institute (R21CA184788 to Q.P.D.), the Welch Foundation (A-1810 to V.M.G.), Pew Charitable Trusts (Pew Scholars Program in Biomedical Science award no. 50350 to D.C.B.)), AIRC Italy (IG 17118 to R.P.), the Florida Department of Health Bankhead-Coley Cancer Research Program (9BC07 to G.M.D.), the Breast Cancer Research Foundation, Susan G. Komen Greater New York City (L.T.V.), the US Department of Army (W81XH-20-1-0754 to L.V.A.), the CSHL Cancer Centre Support Grant (CA45508 to N.K.T.) and the V Foundation Scholar Award (3C59 8ABS 3424 3BDA to D.C.B.) V.M. was supported by the Center on the Physics of Cancer Metabolism through award number U54CA210184 from the National Cancer Institute, and also by National Cancer Institute award R01 CA257254-01A1 (V.M. and L.T.V.). S.G. received support from NIDDK R01-DK-071111 and NIDDK Center grants, P30-DK-41296 and P30-DK-020541 and NCI Center grant P30-CA-13330. A.I.B. is funded by the National Health and Medical Research Council of Australia. C.J.C. is a CIFAR Fellow.

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All authors contributed to discussion of the content. C.J.C. outlined the article. C.J.C., E.J.G., M.J.P., D.C.B., V.M.G., Q.P.D., L.T.V., S.G.K., A.I.B., A.C. and M.L.S. wrote portions of the article. E.J.G., D.C.B. and C.J.C. reviewed and edited the article before submission. C.J.C. and D.C.B. designed the figures.

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Correspondence to Donita C. Brady or Christopher J. Chang.

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Competing interests

N.K.T. is a member of the Scientific Advisory Board of DepYmed Inc. V.M.G. is listed as an inventor on the patent application PCT/US2019/041571 submitted by Texas A&M University entitled “Compositions for the treatment of copper deficiency and methods of use”. D.C.B. holds ownership in Merlon Inc. A.I.B. holds equity in Alterity Biotechnology Ltd, Cogstate Ltd, Mesoblast Ltd and Collaborative Medicinal Development LLC and is a paid consultant for Collaborative Medicinal Development Pty Ltd. L.T.V. is a consultant for Berg Pharma, Osmol Therapeutics and Sema4, serves on the advisory board of Seattle Genetics and Immunomedics/Gilead, and receives research funding from Genentech, Arvinas, and Oncotheraphy Sciences. E.J.G, A.C., P.A.C., J.R.C, G.M.D., Q.P.D., K.J.F., S.G., S.G.K., S.L., V.M., M.J.P., R.P., M.R., M.L.S., L.V.A., D.X., P.Y. and C.J.C. declare no competing interests.

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Ge, E.J., Bush, A.I., Casini, A. et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer 22, 102–113 (2022). https://doi.org/10.1038/s41568-021-00417-2

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