Macrophage-induced ferritin expression protects pancreatic cancer cells from ferroptosis.

Abstract

Reactive oxygen species (ROS) drive pro-tumorigenic signaling but also promote lipid peroxidation and ferroptosis, making ROS regulation critical during high oxidative stress stages of tumor progression, such as metastasis. Loss of the antioxidant TIGAR in pancreatic ductal adenocarcinoma (PDAC) cells raises ROS and enhances metastatic behavior but also sensitizes cells to ferroptosis. To understand how TIGAR-null cells survive to metastasize, we examine the role of macrophage infiltration, which is increased in TIGAR-null tumors. Co-culturing TIGAR-null PDAC cells with macrophages protects them from ferroptosis. The tumor cells induce macrophage IL-6 secretion, which leads to the activation of STAT3 and upregulation of the iron-sequestering protein ferritin (FTH1) in cancer cells. FTH1 depletion in TIGAR-null cells restores ferroptosis sensitivity and reduces lung metastasis. These results suggest that the outcome of increased ROS in tumors may depend on the activation of mechanisms that selectively prevent ferroptosis while preserving ROS-induced oncogenic signaling and metastasis-promoting pathways.