Investigating the role of membrane transporters in the adaptation of cancer cells to an acidic microenvironment

Abstract

As regulators of nutrient uptake, efflux, and compartmentalization, solute carrier (SLC) transporters have a significant impact on cellular metabolism, and as the metabolic interface between the cell and its environment, they are well-placed to enable cancer cells to adapt to the tumour microenvironment. While adaptations to a hypoxic microenvironment are well characterised, less is known about acidosis- specific adaptations. We hypothesised that SLC expression signatures of cancer cells change in response to acidosis, to facilitate metabolic adaptations and survival. We aimed to characterise changes in SLC expression patterns that are specifically associ- ated with acidosis. We used a computational approach to identify samples within the TCGA database with a more or less acidic microenvironment, using transcriptional ‘proxy’ signatures and interrogated differential SLC expression in these samples. The creatine transporter SLC6A8 was upregulated in more ‘acidic’ tumours, especially in lung (LUAD) and colon adenocarcinoma (COAD). This coincided with upregulation of the glucose transporter SLC2A1 and lactate transporter SLC16A13, suggesting SLC6A8 is associated with a more glycolytic phenotype. Analysis of publicly avail- able single-cell transcriptomics data revealed SLC6A8 is predominantly expressed on cancer cells in LUAD clinical samples, and that the transporter is upregulated in late- versus early-stage LUAD. In vitro however, we did not observe acidosis-specific effects of creatine on cancer cell proliferation. In parallel, we investigated the effect of an acidic microenvironment on a panel of lung and colorectal cancer cell lines. Lung lines showed a stronger transcriptional response to acidosis, and a ‘LUAD in vitro acidosis signature’ (LIVAS) was iden- tified. Clinically, LIVAS was associated with a favourable prognosis, and was neg- atively correlated with a hypoxic transcriptional signature. Interestingly, SLC6A8 was downregulated in lung cancer cell lines cultured in acidic conditions. The same was true of glycolytic enzymes and the glucose transporter SLC2A1. This data suggests acidosis in the absence of hypoxia could promote a less glycolytic and sub- sequently less aggressive phenotype in lung cancer.