Uncovering the role of flavin-containing monooxygenase 4 in lung adenocarcinoma: a new protector against ferroptosis
Antonio Maraver
Montpellier Cancer Research Institute (IRCM), Montpellier, France
During the characterization of a new mouse model of lung adenocarcinoma developed in our lab, we revealed a largely unknown protein in lung cancer, the flavin-containing monooxygenase (FMO) 4. We first demonstrated that FMO4 is highly expressed in tumor samples vs healthy lung tissue in four different genetic engineered mouse models that together cover 50% of the oncogenic driver mutations in human lung adenocarcinoma. We then showed that FMO4 is highly expressed in human lung cancer, it is amplified in 3 to 8% of patients with lung adenocarcinoma, and its expression correlates with poor survival in a subset of lung adenocarcinoma patients. We also found that reactive oxidative species (ROS) induced FMO4 expression and that FMO4 knock-down strongly decreases growth of human lung adenocarcinoma cell lines with concomitant increase in ROS levels. More specifically, FMO4 loss of function sensitizes to ferroptosis, a specific cell death with important implications in immunotherapyIn summary, we identified FMO4 as a new tumor promoter protein in lung adenocarcinoma protecting against ferroptosis.