High-fat diet regulates granulocyte metabolism and function in pancreatic cancer

Abstract public domain (NIH RePORTER)

Abstract: Epidemiological studies have highlighted a close relationship between pancreatic cancer mortality and obesity. Approximately 40% of cancer-related deaths in the US have been attributed to obesity. Obesity-induced, in particular visceral fat-induced, inflammation regulates signaling networks that influence tumorigenic pathways in pancreatic cancer. Lard-based high-fat diet, a major component of the American standard diet, plays a key role in obesity in the US population. At present, pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge for therapeutic interventions owing to the resilience of tumor cells even under the harsh environment through metabolic adaptations. PDAC tumor cells upregulate fatty acid metabolism to support its sustenance and metastatic spread. This reliance on fats/lipids may be further amplified in patients following high-fat diets. Thus, we assessed the impact of a lard-based high-fat diet, started prior to tumor cell implantation, on tumor growth in an orthotopic model of pancreatic cancer. We observed a significant alteration in the Gr1+ granulocyte component of systemic immune system at a distant niche and aggressive tumor burden in mice fed on the high-fat diet, as compared to mice fed on a calorie-matched control diet. This two-pronged impact of the high-fat diet at the systemic and local tumor microenvironment suggests that a better understanding of the mechanism through which a high-fat diet alters the anti-tumor responses in the PDAC model will help develop diet-based therapeutic interventions for the better management of PDAC patients in the long run. Thus, in specific Aim 1, we will first assess the impact of a lard-based high-fat diet on granulocyte cell metabolism and immunosuppressive function at the systemic niche. In Specific Aim 2, we will interrogate how high-fat diet-induced granulocytes attenuate the systemic anti-tumor response against pancreatic tumors by focusing on the metabolic pathways that are altered in the anti-tumor immune cells. Finally, Specific Aim 3 will investigate the mechanism through which high-fat diet-induced granulocytes aid in tumor growth by modulating tumor cell metabolism in the presence of excessive fat. Overall, this conceptually innovative proposal will allow an understanding of the consequence of a high fat-based diet on systemic anti-tumor immunity and tumor metabolism in PDAC. Animal models are required for the proposed study to determine the impact of a high-fat diet on anti-tumor immune responses in a more physiologically relevant system. Immune responses are systemic processes that can be studied only in a living system, such as an animal model. Furthermore, the effect of diet on the splenic microenvironment requires the presence of the spleen in the mouse model.

Public health relevance public domain (NIH RePORTER)

Narrative: A lard-based high fat diet amplifies the pancreatic tumor burden in our preclinical models. Our proposal will investigate the contribution of high-fat diet-expanded granulocytes in facilitating tumor growth. We will also investigate the contribution of these cells in subverting anti-tumor immune functions in systemic niches and promoting tumor cell reliance on lipid metabolism.