Project Details

Description

ABSTRACT Rapid fermentation of glucose to lactate (the ?Warburg effect?) was the first molecular characteristic assigned to 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 as macropinocytosis and autophagy. While these cellular capabilities play a critical role, metabolically, tumors ultimately depend on circulating nutrients provided by the host. The extent to which tumors generate energy and biomass building blocks from a few preferred circulating nutrients like glucose, versus uptake diverse 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 serine intake. Which contributes more?circulating serine from the diet or serine synthesized in the tumor? While 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 have surprisingly observed that consumption of circulating nutrients by tumors is profoundly different from that of cultured cancer cells. We have also surprisingly observed that host autophagy is important for sustaining circulating nutrients and for the growth of implanted tumors (where autophagy remains intact). These findings highlight the potential for host metabolic processes to impact tumor growth. What are the critical circulating nutrients for tumors? How is host metabolism altered by autophagy deficiency? Which are the critical changes that impair tumor growth? More broadly, how can tumor dependency on host metabolism be exploited therapeutically? To address these questions, we will employ state-of-the-art isotope tracer techniques to murine tumor models of lung cancer and melanoma. Specifically, we will address the role of 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 lung cancer and melanoma growth. We hypothesize that, rather than using glucose and glutamine as their primary 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 hypothesize that host autophagy is required to maintain circulating nutrients to support tumor growth. Aim 3: Assess the therapeutic potential of modulating circulating metabolites. We hypothesize that decreasing circulating levels of nutrients including arginine, methionine, and glycine will have anti-tumor activity.
StatusFinished
Effective start/end date8/7/126/30/20

Funding

  • National Cancer Institute: $458,236.00
  • National Cancer Institute: $444,948.00
  • National Cancer Institute: $466,524.00
  • National Cancer Institute: $428,527.00
  • National Cancer Institute: $476,594.00
  • National Cancer Institute: $440,730.00
  • National Cancer Institute: $434,619.00
  • National Cancer Institute: $480,941.00

ASJC

  • Oncology
  • Cancer Research

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