Research Projects

Pancreatic cancer (PC) is one of the most leading causes of mortality primarily because of a complex etiology. Interestingly, during the time of diagnosis a vast majority of PC patients have diabetes. Data from clinics also show a positive correlation between hyperglycemia and PC progression. Herein, while the effect of nutrient deprivation on PC cell adaptation is relatively well-explored, how high glucose (HG) complicates PC progression is comparatively neglected. Existing data provides hints towards altered metabolism fueling PC progression; however, the preferential dependence of PC cells on specific substrates and corresponding pathways to meet their bio-energetic needs under HG is poorly understood. Interestingly, upon culture of PC cells under chronic HG we observed an elevated level of cellular homeostatic process autophagy compared to normal glucose exposure; autophagy is known to play a key role in energy metabolism and redox homeostasis. Furthermore, HG also resulted in increase in levels of a key enzyme involved in non-canonical glutamine metabolism often utilized by highly proliferative cells- glutamic-oxaloacetic transaminase1 (GOT1). It is known to facilitate NEAA generation and maintain NADPH levels- thus redox balance. Interestingly, coupled to an increased autophagy and GOT1 under HG, we also observed an up-regulation of a novel long non-coding RNA- YIYA (LINC00538), located on a cancer susceptibility locus. Very few reports exist on YIYA; a study from 2018 hints towards its possible role in promoting glycolysis in breast cancer cells; while a 2020 publication demonstrates its function in colon cancer cell proliferation through regulation of epigenome. Interestingly, our experiments show that siRNA-mediated knockdown of YIYA results in reduced autophagy and GOT1 expression; this is coupled to a compromise of cell proliferation. Based on the above line of evidences we hypothesize that YIYA acts as a key regulatory molecule controlling PC metabolic dependency under HG. However, the molecular mechanism of action of YIYA, and how it integrates with autophagy, glucose/glutamine metabolism and redox homeostasis, regulating the bioenergetic needs of PC cells under HG is unexplored. Interestingly, our in silico analysis hints that YIYA can putatively act as a sponge for multiple microRNAs that target genes involved in autophagy or metabolism. This project therefore plans to experimentally validate the metabolic dependencies of PC cells under HG and thereafter characterize the role of YIYA in regulating the same. Given that PC is an aggressive malignancy that can utilize unorthodox strategies for energy acquisition, understanding the unique metabolic arrangements and its control can provide novel therapeutic avenues.