Diet-mediated regulation of fatty acid saturation impacts cancer progression and therapy responses.

Project Summary/Abstract Many “anti-cancer” diets are promoted in popular culture for cancer prevention and treatment, reflecting the enthusiasm of patients, clinicians, and researchers alike for using diet to improve patient prognosis. Many of these dietary recommendations, however, are poorly supported by scientific evidence. While diet is a known contributor to cancer risk, how diet influences survival in patients who already have cancer is poorly understood. This is a key distinction because many patients are only motivated to make dietary changes after receiving a cancer diagnosis. Moreover, because dietary advice for patients must be given in the context of other treatment strategies, it is important to determine how diet might enhance or antagonize standard-of-care and emerging cancer therapies. Therefore, there is a critical need to define the molecular mechanisms that underlie dietary effects on cancer progression and therapy before it will be possible to integrate diet effectively into cancer treatment. Uncovering these mechanisms will transform precision nutrition therapeutic approaches, which aim to tailor dietary changes with particular therapies to target specific tumor types. Recent work in cancer metabolism has shown that changes to nutrient levels in the tumor microenvironment are key to determining the impacts of dietary interventions on tumor metabolism, growth, and responses to therapy. Interactions between whole-body and tumor lipid metabolism have a central role in linking diet with cancer progression. Lipids are synthesized from fatty acids, which can be saturated, monounsaturated, or polyunsaturated, depending on the number of double bonds they contain. Cellular fatty acid saturation is tightly regulated to maintain membrane structure and cellular function. Previous data shows that dietary manipulations can alter the balance between saturated and unsaturated fatty acids within tumors. The proposed research will define the mechanisms by which diet dysregulates tumor fatty acid saturation states to influence tumor progression and therapy responses. Mouse pancreatic and lung cancer models will be used to examine: (1) how a caloric restriction diet alters tumor-intrinsic polyunsaturated fatty acid metabolism, thereby defining dietary contexts under which this pathway can be therapeutically targeted; (2) how excessive saturated fatty acid consumption induces lipotoxic stress in tumors and generates resistance to cancer therapy, the reversal of which could be a strategy to enhance therapy responses; and (3) how manipulating the fat type in diets alters tumor metabolism and growth in a predictable manner by providing tumors with different relative amounts of saturated, monounsaturated, and polyunsaturated fatty acids, leading to dietary fat type-associated metabolic dependencies that can be therapeutically exploited. These studies will define the metabolic mechanisms underlying how diet-induced changes to whole-body and tumor lipid metabolism interact with cancer therapies. The expected outcomes will set the foundation for the improved design of future translational studies that use dietary interventions as an assistive therapy for cancer treatment.