Title: The critical role of cysteine import and metabolism in pancreatic cancer
Description: Cancer cell metabolism is reorganized around the needs of proliferating cells, particularly the management of organic metabolites and the balance of redox state. Here, we show that pancreatic cancer requires exogenous sources of cysteine for tumor growth and maintenance due to its critical role in redox balance. Using a multidisciplinary approach, we find that cancer cells rely on imported cystine (oxidized cysteine) to detoxify lipid reactive oxygen species (ROS) and avert ferroptosis, a form of non-apoptotic cell death. Cystine–derived glutathione was necessary for this protection, but its depletion was not sufficient to induce ferroptosis. Correspondingly, genetic inactivation of system xc–, the cystine/glutamate antiporter, in established pancreatic tumors induced stabilization or regression, extending survival in an autochthonous mouse model. We observed distinctive lesions of non-apoptotic cell death that may represent an in vivo manifestation of ferroptosis, highlighting a novel, cancer-specific dependency on a potentially druggable membrane channel.