Lack of tumor-derived LCN2 sensitizes pancreatic cancer cells to ferroptosis induction.

Lipocalin 2 (LCN2) is upregulated in many cancers, including pancreatic ductal adenocarcinoma (PDAC), and contributes to tumor development. LCN2 regulates microbial composition, which can influence PDAC outcomes, and has been implicated in ferroptosis resistance in several cancer types. However, the role of tumor-derived LCN2 in mediating ferroptosis and the tumor microbiome in PDAC remains unclear. Here, we show that human PDAC tumors with high LCN2 expression have altered expression of genes involved in ferroptosis, oxidative stress responses, and microbial regulation. Loss of LCN2 in PDAC cells dysregulates ferroptosis-associated pathways, increases lipid peroxidation, and sensitizes cells to ferroptosis induction. In orthotopic PDAC models, the ferroptosis inducer imidazole ketone erastin (IKE) promoted tumor growth in Lcn2-expressing tumors, whereas this effect was absent in tumors lacking LCN2. In addition, tumor-derived Lcn2 expression and ferroptosis induction were associated with distinct changes in the pancreatic tumor microbiome. Overall, these findings identify tumor-derived LCN2 as an important modulator of ferroptotic stress responses in PDAC and suggest that inhibition of tumor-derived LCN2 may enhance susceptibility to ferroptosis-based therapeutic strategies.