Examining Lactate as a Fuel Source in Human Non-Small Cell Lung Cancer

Abstract

Altered metabolism is a hallmark of cancer. Metabolic pathways such as glycolysis are enhanced in malignant tissue and can support the accelerated growth and proliferation of cancer cells. A longstanding dogma of cancer metabolism is that glucose is aerobically metabolized to lactate, as opposed to being oxidized in the TCA cycle. Additionally, lactate is thought to be excreted as a waste product by tumor cells. However, the metabolic behavior of cancer cells has been primarily studied in cultured cell systems rather than in bona fide tumors. Though useful to study the influence of intrinsic factors on metabolism, these systems do not account for extrinsic influences on metabolism that occur in vivo. In this work we study cancer metabolism in vivo through intra-operative nutrient infusions in patients with non-small cell lung cancer. Using 13C-stable isotope tracing, we found that glucose is highly oxidized in tumors compared to surrounding benign lung tissue. Next, we observed that lactate, in addition to glucose, can be used as a nutrient source by lung tumors. We examine the molecular mechanisms of this phenomenon in cell and animal systems using siRNA and CRISPR-mediated knockdown of the lactate transporters MCT1 and MCT4. These clinical observations highlight new aspects of in vivo cancer metabolism, which may lead to the development of new biomarkers or therapeutic opportunities.