Iron supplementation rescues anemia of chronic disease in pancreatic ductal adenocarcinoma

Pancreatic cancer is a devastating malignancy that is rising in incidence and has nearly universal poor outcomes. We find rates of iron deficiency are high in pancreatic cancer patients and track with the high prevalence of anemia in these patients. From an evolutionary perspective, anemia of chronic disease is a condition seen where our bodies respond to an inflammatory insult, such as an infection, by sequestering iron from circulation to store the iron in peripheral tissues, such as muscle, to make this iron unavailable for pathogens. Our recent preliminary data suggest pancreatic cancer may act as the inflammatory stimulus to cause iron dysregulation and anemia. Analysis of a large cohort of pancreatic cancer patients shows both iron and hemoglobin decrease early in pancreatic cancer patients, suggesting of dysregulated iron metabolism. When pancreatic cancer is modeled in mice, decreases in hemoglobin and iron are also observed, as are increases in circulating hepcidin. Interestingly, supplementing mice with pancreatic cancer with iron improves anemia. Mechanistically, we want to understand why mice with PDAC develop anemia and analyzed Ter119-expressing erythrocyte differentiation and maturation in the bone marrow. We found that there is no defect in erythroid maturation in PDAC mice therefore its unlikely that defective erythropoiesis is the cause for anemia in PDAC. We also profiled Ter119-expression on the surface of F4/80-positive macrophages as a measure of hemophagocytosis and found that there is decreased Ter119-positive macrophages in PDAC so hemophagocytosis in the bone marrow is not the caused of anemia in PDAC. We find that iron-sequestering proteins such as hepcidin are increased throughout PDAC progression and iron sequestration in tumors and we find iron sequestration by many different cell types and tissues during PDAC. Hepcidin is known to cause iron sequestration in macrophages, which are the largest source of iron recycling and supply for heme and hemoglobin synthesis in the body. Furthermore, we observed decreased macrophage numbers in the bone marrows of PDAC mice. Hence, we proposed that PDAC leads to reduced iron-recycling by macrophages and this causes anemia of chronic disease. Therefore, iron supplementation is sufficient to rescue anemia in PDAC.