Impact of the MCT1-mediated lactate import on the phenotype of pancreatic ductal adenocarcinoma cells

One of the emerging phenotypes during metabolic reprogramming in cancers is the aggressive reverse Warburg phenotype, which correlates with poor prognosis in PDAC. A major metabolic driver of this phenotype is lactate, the highly abundant end product of glycolysis during Warburg metabo­lism. Lactate can be exported through MCT4 out of Warburg cells that excessively run glycolysis or can be imported through MCT1 by those cells that are able to run oxidative metabolism largely for energy production. Lactate import in these cells results in the develop­ment of reverse Warburg phenotype.

This study revealed that lactate import under glucose deficiency not only creates a reverse Warburg phenotype but also enriches PDAC cells for a more stem cell-like phenotype along with high self-renewal capacity. This study showed that cells particularly upregulate the reprogramming factor KLF4, on one hand and lower the pluripotent cell marker Sox2, on the other hand. This study also revealed an­other metabolic pressure leading to the development of the reverse Warburg metabolism in PDAC cells. Here, we showed that the MCT1-mediated lactate import is increased under glutamine deficiency in a NRF2-dependent fashion. In addition, lactate was shown to exhibit growth ad­vantages for PDAC cells, by releasing them from cell cycle arrest they face when glutamine availability is low. This unleashing effect of lactate utilization towards more proliferation de­pends on a compensatory mechanism by which lactate allows PDAC cells to overcome oxi­dative stress emerging from glutamine starvation. Indeed, this work provides insights into the potential use of therapeutic strategies to increase the drug therapy as well as to reduce tumor relapse.