Cancer is essentially a disease in which cells have lost their normal checks on cell proliferation. Cancer cells also have evolved to evade elimination by the immune system, the body’s defense mechanism against foreign invaders. Our research is focused on deciphering the biological perturbations that underlie the development and progression of cancer, with specific interest in studying: 1.) how alterations in cellular metabolism and energy use contribute to tumorigenesis, and 2.) how intrinsic metabolic control shapes immune responses.
Major questions we are investigating include:
One of the fundamental biochemical programs influenced by T cell activation is cellular energy metabolism. Naïve T cells encountering processed antigen and co-stimulatory signals from antigen presenting cells (APCs) switch to a program of anabolic growth and biomass accumulation to promote clonal expansion of antigen-specific T cells. This switch from a quiescent to proliferative state dictates increased demand for ATP and biosynthetic precursors for growth. Activated effector T (Teff) cells reprogram their metabolic activities to meet the increased metabolic demands of cell growth, proliferation and effector function.
Our research in this area is focused on understanding the key metabolic pathways required by effector T cells for effective immune function. We combine metabolomics with RNA and protein profiling to better understand the essential metabolic nodes that support T cell function. Our current interests are in understanding the impact of serine, glycine and one-carbon (SGOC) metabolism and other branch points from glycolysis and the TCA cycle that impact T cell proliferation and effector function. We also are investigating the impact of nutritional interventions to identify key metabolites that support optimal T cell function in vivo.
The ability to engage in increased glycolytic metabolism may be advantageous for growth of cancer cells beyond the ability to rapidly generate energy and suppress apoptosis. This raises a crucial question — what are the metabolic pathways important for growth in proliferating cancer cells?
My research group is focused on investigating how signal transduction pathways can redirect metabolic pathways for biosynthesis to enable cell proliferation. Our group focuses on defining the molecular regulators of this process, with particular attention on how the LKB1/AMPK nutrient energy sensing pathway and microRNAs regulate this process.
Increased metabolic potential, while supportive of unchecked growth, poses a distinct metabolic challenge for tumor cells. Once a growing tumor outstrips its nutrient supply, it must enact strategies to maintain cellular bioenergetics. Thus, how tumors engage strategies of metabolic adaptation to survive stress may contribute to cancer progression and outcome (i.e., metastasis). Our research in this area has focused on the metabolic regulator AMPK and its role in promoting adaptation to metabolic stress. More recent work has identified pathways that tumor cells use to proliferate when glucose is limiting, which includes co-opting parts of gluconeogenesis to use TCA cycle intermediates for biosynthesis. Our future efforts are focused on identifying novel pathways that mediate cellular adaptation to stress.
T cells play important roles in cancer immunosurveillance and anti-tumor immunity. Metabolic constraints in the tumor microenvironment can negatively impact anti-tumor T cell responses, in part by competition of tumor infiltrating lymphocytes (TIL) with tumor cells for available nutrients such as glucose. Engagement of receptors such as PD-1 on activated T cells reduces T cell responsiveness and promotes T cell “exhaustion”. Our work focuses on understanding the metabolic constraints that the tumor microenvironment imposes on T cell expansion and function, and whether we can reverse the negative effects of the tumor microenvironment on T cells to enhance anti-tumor immunity.
We also are investigating the impact of metabolic control pathways on the control of inflammation. We have recently found that deregulation of LKB1 in T cells is sufficient to promote gastric tumor formation in mouse models of Peutz Jeghers Syndrome, a cancer predisposition syndrome that arises in patients with LKB1 mutations. This raises the possibility that immune cell-mediated inflammation drives the formation of these cancers. We are actively exploring how LKB1-mediated inflammation control impacts tumor progression.