Cells normally require abundant energy and nutrients to grow and replicate. However, cancer cells can often manipulate their signaling pathways to allow them to grow in the absence of efficient energy production or the necessary growth signals. We are working to understand the links between metabolism and cancer in an effort to add to the growing body of knowledge with respect to potential avenues or targets for therapeutics. Our work centers around the AMP-activated Protein Kinase (AMPK), a serine-threonine kinase conserved in all eukaryotes that is critical for sensing intracellular energy levels and regulating cell growth under low energy conditions. Activated AMPK phosphorylates a broad set of downstream targets, which play roles in cell growth, autophagy, transcriptional regulation, and metabolic programs, providing mechanisms for cells to arrest their growth when nutrients are limiting.
AMPK impinges on cell growth in large part through its negative regulation of mTORC1 by phosphorylation of the essential mechanistic Target of Rapamycin (mTOR) binding partner Raptor and the negative mTORC1 regulator TSC2. However, the physiological and pathological contexts when this ancient metabolic checkpoint of AMPK suppression of cell growth occurs in the intact organism remain largely unknown. We are interested in characterizing the role of AMPK regulation of substrates in vivo, focusing in the short-term on AMPK’s regulation of mTORC1 through Raptor and TSC2 in tumorigenesis and metabolic disease. These studies will expand the knowledge of AMPK’s regulatory role to complex intact organisms and define the in vivo context of how AMPK functions. These studies will utilize novel phosphorylation mutant mouse models described previously (Van Nostrand, et al, 2020).
Finally, pharmacological activation of AMPK using the anti-diabetic drug metformin has been associated in large epidemiological studies with a reduction in the risk for metabolically-linked cancers. Recently, it has become appreciated that metabolic disease (obesity, diabetes) are emerging risk factors that affect an increasingly large percentage of the population and are causing the incidence of metabolically-linked cancers, such as hepatocellular carcinoma (HCC), to rise. Notably, HCC caused by metabolic disease is difficult to combat since these risk factors are very common in 30-40% of adults and have no cure. Developing prevention strategies that target the underlying metabolic diseases would therefore have multiple critical benefits clinically. Unfortunately, although metabolic disease is tightly linked to HCC, the molecular triggers that initiate HCC in the context of these metabolic perturbations are not fully understood. Thus, we are interested in defining the role of AMPK and AMPK activation in the development of HCC, which could define novel new therapeutic interventions for HCC prevention.
Overall, our research is aimed at studying the role of metabolic checkpoints triggered by AMPK and mTOR signaling in cancer and metabolic disease. We employ a variety of biochemical, cell-biological, and genetic mouse models to dissect these biological processes. A deeper understanding of the interrelationship between cancer and metabolic disease will inform on how cells respond to energy stress and metabolic changes to suppress tumorigenesis and aid in establishing effective preventative and therapeutic strategies for cancer patients.