The Genomic Analysis of Lactic Acidosis and Acidosis Response in Human Cancers

Abstract

The tumor microenvironment has a significant impact on tumor development. Two important determinants in this environment are hypoxia and lactic acidosis. Although lactic acidosis has long been recognized as an important factor in cancer, relatively little is known about how cells respond to lactic acidosis and how that response relates to cancer phenotypes. We develop genome-scale gene expression studies to dissect transcriptional responses of primary human mammary epithelial cells to lactic acidosis and hypoxia in vitro and to explore how they are linked to clinical tumor phenotypes in vivo. The resulting experimental signatures of responses to lactic acidosis and hypoxia are evaluated in a heterogeneous set of breast cancer datasets. A strong lactic acidosis response signature identifies a subgroup of low-risk breast cancer patients having distinct metabolic profiles suggestive of a preference for aerobic respiration. The association of lactic acidosis response with good survival outcomes may relate to the role of lactic acidosis in directing energy generation toward aerobic respiration and utilization of other energy sources via inhibition of glycolysis. This “inhibition of glycolysis” phenotype in tumors is likely caused by the repression of glycolysis gene expression and Akt inhibition. Our study presents a genomic evaluation of the prognostic information of a lactic acidosis response independent of the hypoxic response. Our results identify causal roles of lactic acidosis in metabolic reprogramming, and the direct functional consequence of lactic acidosis pathway activity on cellular responses and tumor development. The study also demonstrates the utility of genomic analysis that maps expression-based findings from in vitro experiments to human samples to assess links to in vivo clinical phenotypes. It is well recognized that tumor microenvironments play an important role in modulating tumor progression in human cancers. Although previous studies have highlighted the importance of hypoxia, there is limited knowledge on the effects of other components in tumor microenvironments. Therefore, we use gene expression to compare and analyze how cells respond to lactate, acidity, and hypoxia, as well as how these responses can be utilized to predict the clinical outcomes of patients with breast cancers. We uncover an unexpected association with better clinical outcome of the strong lactic acidosis and acidosis response in breast cancers as a result of their abilities to inhibit glycolysis and favor oxidative phosphorylation for energy generation. This effect is caused by not only the repression of the gene expression of glycolysis genes but also the inhibition of Akt activation of cells exposed to lactic acidosis and acidosis. In conclusion, we propose that lactic acidosis and acidosis to be considered as independent prognostic factors for human cancers.