Pancreatic ductal adenocarcinoma causes altered whole-body iron distribution

Anemia of chronic disease is a prevalent form of anemia that occurs in patients with acute or chronic immune activation associated with multiple diseases, including cancer. A hallmark of anemia of chronic disease is disturbed iron homeostasis, where iron uptake and retention within the reticuloendothelial system and within peripheral tissues is increased to divert iron away from circulation and into storage sites, limiting availability for erythropoiesis. We observe in PDAC mice and patients that they exhibit anemia of chronic disease and find in different mouse models of PDAC that iron availability is decreased in circulation and that instead iron is being stored in peripheral tissues such as muscle, pancreas, liver, spleen, and many other organs and tissues. Our laboratory has shown that impaired exocrine function is a key driver of peripheral tissue wasting in PDAC and that decreased pancreatic enzyme secretion can be used for early diagnosis of PDAC. Therefore, we wondered whether intestinal iron absorption is decreased in PDAC and surprisingly found increased intestinal iron absorption in PDAC due to upregulation of the enterocyte iron importer DMT1 and iron exporter Ferroportin. Iron uptake from diet and iron sequestration into peripheral tissues can be studied through isotope tracing experiments. Fe56 is the predominant naturally abundant iron isotope so we used an Fe57-infused diet to study the kinetics of Fe57 intake and found that Fe57 is less abundant in the serum from PDAC mice compared to wildtype mice, suggesting that iron is quickly sequestered from circulation and into peripheral tissues. We are now focusing on identifying the regulators of increased intestinal iron absorption and iron sequestration in the context of PDAC.