Grant Abstract: Polyunsaturated fatty acids supplementation and Lipocalin 2 blockade in preventing pancreatic cancer

Grant Number: 3R01CA223204-05W1
PI Name: Cruz-Monserrate
Project Title: Polyunsaturated fatty acids supplementation and Lipocalin 2 blockade in preventing pancreatic cancer

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that lacks successful preventive measures where the pro-inflammatory molecule lipocalin 2 (LCN2) is upregulated. Our laboratory showed that the tumor- derived protein LCN2 is elevated in the blood and tumors of PDAC patients and that it promotes inflammation in the tumor microenvironment (TME). Recently, it was suggested that LCN2 could inhibit ferroptosis due to its iron binding properties. Ferroptosis is an iron dependent form of non-apoptotic cell death characterized by excessive peroxidation of polyunsaturated fatty acids (PUFAs) catalyzed by iron in the cells. PUFA oxidation is necessary for ferroptosis induction, but there is limited evidence on the potential of a PUFA supplementation to induce cancer ferroptosis. To our knowledge, there are only a few in-vitro studies in other cancer types that explore the potential of using PUFA supplementation to promote ferroptosis. PUFA supplementation studies containing n-3 docosahexaenoic (DHA) and eicosapentaenoic (EPA) are widely available and have shown beneficial effects in health. Understanding whether PUFA supplementation could be used as a preventive mechanism for PDAC development will lay the groundwork to develop efficient preventive strategies targeted for PDAC high-risk individuals. We propose to fill these gaps in knowledge by 1) determining whether a PUFA supplementation including DHA and EPA, will sensitize early pancreas cancer cells to ferroptosis and prevent the development of PDAC; and 2) whether the effectiveness of this intervention will be enhanced by modulating LCN2 levels. HYPOTHESIS: PUFA dietary supplementation in combination with LCN2 antibody blockade will promote ferroptosis by increasing lipid peroxidation, and will prevent the formation of early lesions of PDAC and progression of these lesions into cancer. In order to test this hypothesis, we aim to determine whether a PUFA dietary intervention prevents tumor development by promoting ferroptosis and whether the effect can be enhanced by decreasing LCN2 levels. IMPACT: Data from this study will inform us on whether a PUFA supplementation could prevent PDAC by promoting ferroptosis, and whether LCN2 mediates ferroptosis sensitivity. Our study will provide insights to guide new PDAC preventive strategies and dietary supplementation guidelines for patients at risk of this disease. PUBLIC HEALTH RELEVANCE: : Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease, where the inflammatory protein lipocalin 2 (LCN2) is upregulated and promotes tumor growth. This protein seems to inhibit an iron-dependent form of cell death called ferroptosis, which relies on the oxidation of polyunsaturated fatty acids (PUFAs) in the cell. We propose to investigate the potential of a PUFA dietary supplementation in combination with modulation of LCN2 levels to promote ferroptosis and therefore, prevent PDAC development.

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