Acidity is a signature of microenvironment in solid cancers and poses a substantial challenge to the intracellular pH homeostasis of cancer cells. The activity of acid-base transporters of the solute-linked carrier (SLC) superfamily is critical for intracellular pH homeostasis in the acidic microenvironment, by removing the end-products of fermentative metabolism (lactate/protons) and maintaining a favourably alkaline cytoplasm for cell division. Consequently, somatic mutations affecting relevant SLC genes may impact the oncogenic process by either augmenting or decreasing cancer cell fitness under the selection pressure of low extracellular pH. However, the landscape of somatic mutations in acid/base-transporting SLCs across the common types of human cancers had not been analysed systematically until now.
The review by DPhil student Bobby White and Professor Pawel Swietach provides a pan-cancer analysis of somatic mutations in acid/base-transporting-SLCs, and identifies those which are essential for cancer cell survival, or exhibit somatic mutations capable of driving cancer. Specifically, the team shows that the mutation burden of monocarboxylate transporters (of the SLC16 family) is extremely low in human cancers, even when contextualised against other transporters essential for cancer cell survival, such as transporters of nucleotides/nucleosides, glucose, and amino acids. Furthermore, the presence of wildtype (i.e. functional) monocarboxylate transporters could be associated with significantly worse overall cancer survival. The team also found that, among all cancers, tumours of uterine corpus endometrial cancer carried more acid/base-transporting SLC somatic mutations than expected based on their average tumour mutation burden. Among these, somatic mutations in the acid loader SLC4A3 had features consistent with a role in driving oncogenesis. The team’s findings highlight specific contexts for targeting acid-base transporters in order to manipulate the evolutionary course of a patient’s cancer.
Miss White said: “We are thrilled to have extensively characterised the mutational landscape of acid-base transporters in human cancers. Our findings highlight the critical role of intracellular pH homeostasis in tumourigenesis. Indeed, somatic mutations disrupting monocarboxylate transporters (which remove lactate/protons produced by fermentive metabolism) are likely to hamper cancer progression, whilst mutations of SLC4A3 (encoding an acid-loading protein) are likely to augment endometrial cancer progression. More broadly, we provide human tumour data-driven identification of promising research avenues for the targeting of acid-base transport in the clinic.”
The full paper “What can we learn about acid-base transporters in cancer from studying somatic mutations in their genes?” is available to read in Pflügers Archiv - European Journal of Physiology, 24 November 2023, doi: 10.1007/s00424-023-02876-y.