Cancer metabolism research has largely focused on understanding how oncogenic signaling impacts cellular metabolism or how the altered regulation of specific enzymes impinges on metabolite fluxes in cultured cells. At the whole body level, the corruption of signaling and metabolite sensing has principally been addressed in the setting of obesity and diabetes. Despite clear epidemiological links between these states and cancer, it remains unknown if altered metabolic fluxes between normal and malignant tissues can influence tumor cell proliferation, and to what degree whole-body metabolite levels can influence pathways within cells to promote the development or progression of cancer. Understanding these links is critical for successful therapeutic disruption of altered cellular biochemical pathways in the clinic. To identify whole-body metabolite alterations that may predict and/or promote cancer development, we applied a metabolomics-based approach to blood plasma from a large prospective cohort study of pancreatic adenocarcinoma (PDAC) patients. Strikingly, elevations of the three branched chain amino acids (BCAAs) isoleucine, leucine and valine were associated with a greater than two-fold increased risk of future PDAC diagnosis. Initial studies in mouse tumor xenograft models indicate that increasing plasma BCAA levels can enhance pancreatic cancer cell proliferation in vivo. Together, these data suggest that BCAAs (or their derivatives) may promote initiation and/or progression of PDAC. The goal of this project is to determine what role BCAAs play in the pathogenesis of PDAC. To address this question, I propose to: 1) Assess the timing of plasma BCAA elevations and determine whether these changes represent an early whole-body response to cancer 2) Determine if catabolism of BCAAs or their derivatives can contribute to biomass and enhance proliferation of PDAC cells in culture 3) Characterize the role of BCAA metabolism in promoting PDAC cell growth in vivo By addressing these aims I can gain insight into the biological significance of elevated BCAA levels in PDAC. This is needed for physicians to stratify high-risk patients for further tests and may suggest new therapeutic approaches. Additionally, work on this project will foster my development as an independent physician-scientist by placing me at the interface between clinical and basic science investigators. Since our initial observations stem from a large, collaborative, human-based study, I will learn how to translate clinical observations into testable hypotheses that can be investigated using model organisms and basic science techniques. Ultimately, work on this project will train me in the overall approach to address the key translational questions I will focus on later in my career.
Pancreatic cancer represents the fourth leading cause of cancer death in the US and has a dismal survival rate with little improvement over the last several decades. Using a unique panel of blood samples collected from almost 1500 patients, many of whom went on to develop pancreatic cancer, we have identified a signature of metabolic changes that predict future diagnosis. This study will examine the possibility of using this signature in the clinic, as well as investigating how these changes affect pancreatic cancer progression in laboratory models of the disease.
|Mayers, Jared R; Wu, Chen; Clish, Clary B et al. (2014) Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 20:1193-8|