Whole body metabolic alterations as an early event in Kras-Driven cancers

• Main Author: Mayers, Jared Ross
• Other Authors: Matthew G. Vander Heiden.
• Format: Others
• Language: English
• Published: Massachusetts Institute of Technology 2016
• Subjects: Biology.
• Online Access: http://hdl.handle.net/1721.1/101351

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2015. === Cataloged from PDF version of thesis. Vita. === Includes bibliographical references. === Cancer is a disease defined by the uncontrolled proliferation of cells. Using primarily in vitro approaches, researchers have gained critical insight into how different oncogenic mutations alter the regulation of metabolic pathways and shape nutrient utilization to facilitate the acquisition and synthesis of new biomass for daughter cells. These culture systems, however, rely on relatively homogenous cell populations isolated from interactions with normal host tissues and free of the challenges of nutrient acquisition they would face in vivo. Focusing on pancreatic cancer, which is known to have an intricate relationship with normal host metabolism, we asked how early tumors might change whole-body metabolism by examining changes in plasma metabolite levels. In both humans and mice, we identified significant increases in the plasma levels of the branched chain amino acids (BCAAs), leucine, isoleucine and valine, and showed these elevations occurred concomitantly with early invasive cancer. Further experiments in mouse models revealed that increased turnover of peripheral protein stores drove these changes in a pattern reminiscent of cachexia. Interestingly, we also found that a mouse model of non-small cell lung cancer driven by the same genetic lesions as our pancreatic cancer model displayed the opposite plasma BCAA changes. We subsequently demonstrated these changes were the result of tumor cell autonomous differences in BCAA incorporation and catabolism between the tumors of different tissue origins. Non-small cell lung cancers in particular showed an increase in the extraction of nitrogen, a critical component for the synthesis of non-essential amino acids and nucleotides, from BCAAs. Returning to pancreatic cancer, we hypothesized that the limited tumor burden at the time of BCAA elevations indicated that a hormonal factor(s) was likely regulating the process of muscle breakdown. We developed a computed tomography based approach to accurately quantitate muscle volumes longitudinally in mice and conducted an initial screen of known cachexia factors, identifying IL-6 and Activin A as potential candidates that are elevated early in pancreatic cancer. We also conducted preliminary investigations into the mechanism governing tissue turnover in muscle in early disease and our results suggest autophagy may be the primary regulator of this process. Taken together, these data indicate that tumors can induce broad and significant changes in host metabolism and highlight the importance of tumor origin when examining the role of oncogenic mutations in different cellular contexts. === by Jared Ross Mayers. === Ph. D.