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Intracellular pH dynamics and charge-changing somatic mutations in cancer

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Abstract

An unresolved question critical for understanding cancer is how recurring somatic mutations are retained and how selective pressures drive retention. Increased intracellular pH (pHi) is common to most cancers and is an early event in cancer development. Recent work shows that recurrent somatic mutations can confer an adaptive gain in pH sensing to mutant proteins, enhancing tumorigenic phenotypes specifically at the increased pHi of cancer. Newly identified amino acid mutation signatures in cancer suggest charge-changing mutations define and shape the mutational landscape of cancer. Taken together, these results support a new perspective on the functional significance of somatic mutations in cancer. In this review, we explore existing data and new directions for better understanding how changes in dynamic pH sensing by somatic mutation might be conferring a fitness advantage to the high pH of cancer.

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Funding

This study is supported by a National Institute of Health grant CA197855 (D.L.B.) and startup funds from the University of Notre Dame (K.A.W.).

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  1. Harper Cancer Research Institute, Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, 46617, USA

    Katharine A. White

  2. Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, 94143, USA

    Katharine A. White, Kyle Kisor & Diane L. Barber

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White, K.A., Kisor, K. & Barber, D.L. Intracellular pH dynamics and charge-changing somatic mutations in cancer. Cancer Metastasis Rev 38, 17–24 (2019). https://doi.org/10.1007/s10555-019-09791-8

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