Rapid fermentation of glucose to lactate (the “Warburg effect”) was the first molecular characteristic assignedto cancer. Recent years have seen an explosion of interest in the metabolic capabilities of tumor cells,including up-regulated anabolism, redox defense, and alternative routes of nutrient acquisition such asmacropinocytosis and autophagy. While these cellular capabilities play a critical role, metabolically, tumorsultimately depend on circulating nutrients provided by the host. The extent to which tumors generateenergy and biomass building blocks from a few preferred circulating nutrients like glucose, versus uptakediverse nutrients to minimize their own biosynthetic work, remains, however, poorly understood. For example,many tumors upregulate serine biosynthesis. At the same time, tumor growth is sensitive to dietary serineintake. Which contributes more—circulating serine from the diet or serine synthesized in the tumorWhile substantial efforts have been made to understand the essential metabolic pathways within tumor cells,comparatively little effort has gone into understanding the tumor's dependency on host metabolism. We havesurprisingly observed that consumption of circulating nutrients by tumors is profoundly different fromthat of cultured cancer cells. We have also surprisingly observed that host autophagy is important forsustaining circulating nutrients and for the growth of implanted tumors (where autophagy remainsintact). These findings highlight the potential for host metabolic processes to impact tumor growth. What arethe critical circulating nutrients for tumors How is host metabolism altered by autophagy deficiency Whichare the critical changes that impair tumor growth More broadly, how can tumor dependency on hostmetabolism be exploited therapeutically To address these questions, we will employ state-of-the-art isotopetracer techniques to murine tumor models of lung cancer and melanoma. Specifically, we will address the roleof host metabolism in mouse models of K-Ras lung cancer, and B-Raf lung cancer and melanoma:Aim 1: Identify the contributions of circulating nutrients and internal tumor metabolic pathways to lungcancer and melanoma growth. We hypothesize that, rather than using glucose and glutamine as theirprimary substrates, tumors in vivo consume a broad diversity of circulating nutrients, including amino acids,fats, and lactate, thereby minimizing biosynthetic requirements and enhancing metabolic robustness.Aim 2: Determine the mechanism underlying dependence of tumors on host autophagy. We hypothesizethat host autophagy is required to maintain circulating nutrients to support tumor growth.Aim 3: Assess the therapeutic potential of modulating circulating metabolites. We hypothesize thatdecreasing circulating levels of nutrients including arginine, methionine, and glycine will have anti-tumoractivity.
|Effective start/end date||8/7/12 → 6/30/22|
- National Institutes of Health (NIH)
Metabolic Networks and Pathways