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Acid–base transporters in the context of tumor heterogeneity

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Abstract

The copious metabolic acid production and -extrusion by cancer cells render poorly vascularized regions of solid tumors highly acidic. A growing list of proton - and bicarbonate transporters has been suggested to contribute to net acid extrusion from cancer cells, and/or been shown to be dysregulated and favor malignant development in various cancers. The great majority of these roles have been studied at the level of the cancer cells. However, recent advances in understanding of the cellular and physicochemical heterogeneity of solid tumors both enable and necessitate a reexamination of the regulation and roles of acid–base transporters in such malignancies. This review will briefly summarize the state-of-the-art, with a focus on the SLC9A and SLC4A families, for which most evidence is available. This is followed by a discussion of key concepts and open questions arising from recent insights and of the challenges that need to be tackled to address them. Finally, opportunities and challenges in therapeutic targeting of the acid–base transportome in cancers will be addressed.

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Acknowledgements

I am grateful to all members of my lab for stimulating discussions and to E. Boedtkjer, Aarhus University, Denmark, for insightful comments.

Funding

Related work in my lab was funded by the Novo Nordisk Foundation (NNF21OC0069598); The Danish Cancer Society (R269-A15823); The Carlsberg Foundation (CF18-0532; CF20-0491); and Independent Research Fund Denmark (0135-00139B; 0134-00218B).

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  1. Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark

    Stine Helene Falsig Pedersen

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S.F.P. researched, conceptualized, and wrote the review and prepared the illustrations.

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Correspondence to Stine Helene Falsig Pedersen.

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SFP is a co-founder of SOLID Therapeutics.

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Pedersen, S.H.F. Acid–base transporters in the context of tumor heterogeneity. Pflugers Arch - Eur J Physiol 476, 689–701 (2024). https://doi.org/10.1007/s00424-024-02918-z

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