Grant Number:	3U01CA272529-03S1 Interpret this number
Primary Investigator:	Summers, Scott
Organization:	University Of Utah
Project Title:	Ceramides as Novel Drivers of Metabolic Dysfunction and Colorectal Cancer
Fiscal Year:	2024

Summary Diet-induced obesity affects about 40 percent of US women and increases the incidence, morbidity, and mortality of postmenopausal breast cancer (BC). Obesity also increases the risk of large, high-grade tumors, metastasis, and recurrence regardless of menopausal status. Our goal is to contribute to the development of new therapeutic approaches for the treatment of obesity-associated human BC. Our research proposal addresses this by testing whether dietary lipids induce the biosynthesis of ceramides which accelerate BC tumor growth. Supported by published evidence and our own preliminary data, our central hypothesis is that, in settings of chronic dietary lipid overabundance such as obesity, BC cells are wired to utilize free fatty acids (FFA) over glucose to support cancer lipid anabolism, resulting in accelerated tumor growth. Moreover, our data suggests that ceramides dictate this fuel choice by serving as feed-forward signals of fatty acid excess that increase fat utilization and decrease carbohydrate oxidation. We will test our central hypothesis by pursuing two specific aims: 1) to test the hypothesis that ceramide-lowering interventions negate the impact of ketogenic diets or apolipoprotein E knockout on breast cancer growth; 2) to determine whether experimental induction of ceramides alters fuel choice and accelerates breast cancer growth. Our approach, which collectively addresses physiology, adipose biology, and tumor metabolism, is enabled by our combined expertise in ceramides (Dr. Summers), nutrition and metabolic status (Dr. Chaix), adipose tissue biology (Dr. Hilgendorf), and in vivo stable isotope tracing to study tumor metabolism (Dr. Ducker). Together, we have established a system in which BC tumor growth can be accelerated solely by the manipulation of circulating levels of lipids, independent of adiposity and associated metabolic syndrome. This lipid-centric view of tumor metabolism generates strong testable hypotheses for future therapeutic interventions, including the one described herein that ceramides are obligate intermediates that link excessive saturated fats to worsened breast cancer outcomes.





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