Defining sources of nutrient limitation for tumors

Abstract

Tumor growth requires that cancer cells accumulate sufficient biomass to grow and divide. To accomplish this, tumor cells must acquire various nutrients, and growth slows if these metabolites are not obtained in sufficient quantities. Importantly, the metabolic demands of cancer cells can be different from those of untransformed cells, and nutrient accessibility in tumors is different than in normal tissues. Thus, tumor survival and growth may be limited by different metabolic factors than those that are necessary to maintain non-cancerous cells. This dissertation examines sources of nutrient limitation in tumors. We study the role of the amino acid serine in tumor growth and show that endogenous serine availability restrains growth of breast tumors. We also demonstrate that breast cancer and melanoma can overcome physiological serine limitation by upregulating expression of the serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH).

To further study amino acid and nucleotide metabolism in tumor growth, we examine the role of the enzyme methionine synthase (MTR) in tumor progression. MTR is involved in both methionine synthesis and folate metabolism and may be important for tumor progression. We find that MTR is required to maintain intracellular levels of both S-adenosyl methionine and nucleotides, but not methionine. We observe that MTR is dispensable for growth in standard culture media, but essential in media containing the folate source available in blood. Further, MTR is essential for folate metabolism and tumor growth in vivo. The conditional requirement for MTR depending on the source of extracellular folate highlights the importance of understanding which nutrients are available to tumors in vivo, as nutrient accessibility can determine whether a given metabolite or pathway is limiting for tumor growth.

To define the nutrient environment present in tumors, we quantitatively profile the metabolites present in tumor interstitial fluid (TIF). We find that the nutrients available to tumors in TIF differ from those present in circulation. Further, by comparing TIF nutrient levels between murine cancer models, we find that tumor type, anatomical location and animal diet affect local nutrient availability. Together, these studies provide new insight into sources of nutrient limitation in tumors.