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.
Tumors obtain most of their nutritional support for growth from normal tissues of the body through the circulating blood supply, yet what these nutrients are is not clear. Recent evidence suggests that nutrient scavenging pathways of normal tissues in the body contribute nutritional support for tumors, but this is also poorly understood. We propose to identify the nutrients provided by the body that are critical for the growth of lung cancers and melanomas, and to determine their role in tumor growth, as a novel approach to the eradication of these deadly cancers.
|Tsang, Chi Kwan; Chen, Miao; Cheng, Xin et al. (2018) SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation. Mol Cell 70:502-515.e8|
|Morscher, Raphael J; Ducker, Gregory S; Li, Sophia Hsin-Jung et al. (2018) Mitochondrial translation requires folate-dependent tRNA methylation. Nature 554:128-132|
|Lu, Wenyun; Wang, Lin; Chen, Li et al. (2018) Extraction and Quantitation of Nicotinamide Adenine Dinucleotide Redox Cofactors. Antioxid Redox Signal 28:167-179|
|Poillet-Perez, Laura; Xie, Xiaoqi; Zhan, Le et al. (2018) Autophagy maintains tumour growth through circulating arginine. Nature 563:569-573|
|Tanner, Lukas Bahati; Goglia, Alexander G; Wei, Monica H et al. (2018) Four Key Steps Control Glycolytic Flux in Mammalian Cells. Cell Syst 7:49-62.e8|
|Perekatt, Ansu O; Shah, Pooja P; Cheung, Shannon et al. (2018) SMAD4 Suppresses WNT-Driven Dedifferentiation and Oncogenesis in the Differentiated Gut Epithelium. Cancer Res 78:4878-4890|
|Liu, Ling; Su, Xiaoyang; Quinn 3rd, William J et al. (2018) Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab 27:1067-1080.e5|
|Jang, Cholsoon; Chen, Li; Rabinowitz, Joshua D (2018) Metabolomics and Isotope Tracing. Cell 173:822-837|
|Nofal, Michel; Zhang, Kevin; Han, Seunghun et al. (2017) mTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein. Mol Cell 67:936-946.e5|
|Hui, Sheng; Ghergurovich, Jonathan M; Morscher, Raphael J et al. (2017) Glucose feeds the TCA cycle via circulating lactate. Nature 551:115-118|
Showing the most recent 10 out of 89 publications