Altered metabolism is a hallmark of malignancy. Metabolic pathway changes contribute to cancer cell growth, transformation and survival. These differences can be exploited to image tumor tissue and provide predictive information to patients. Importantly, these metabolic differences can also be exploited therapeutically. Thus, understanding cancer metabolism has important implications for pathophysiology and clinical oncology. Progress in translating these studies into new therapies is limited by the fact that much of knowledge in tumor metabolism is derived from studies in cultured cells with unknown relevance to disease biology. Similarly, cell line xenografts may not accurately recapitulate the cellular heterogeneity of a primary tumor. For these reasons, little is known about tumor metabolism in vivo, and the factors that regulate this behavior. My proposal utilizes clinical samples wherein the metabolic behavior of the primary human tumor is evaluated and characterized. These tissues are translated to mouse models, where I will evaluate what metabolic phenotypes are retained, as well as test what intrinsic and extrinsic factors promote metabolic behavior. During the mentored phase of the grant, I will focus on identifying retained/intrinsic metabolic phenotypes, as well as extrinsic factors such as the role of tumor perfusion on nutrient preference. With these insights, I will continue independent research focusing on the molecular details of these factors, to identify combinations of factors influencing cancer metabolism in vivo.
The field of cancer metabolism has had significant clinical impact: imaging modalities, biomarkers, and new therapeutic targets have resulted from studying tumor metabolism in cell culture. However, many findings from cell culture studies have been difficult to replicate in vivo, suggesting additional factors that influence tumor metabolism. In this project I use clinically-matched, patient-derived xenografts to identify the factors that influence tumor metabolism in vivo.