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DelGiorno Lab

Cysteine depletion induces pancreatic tumor ferroptosis in mice

AUTHORS

Badgley MAMichael A , Kremer DMDaniel M , Maurer HCH Carlo , DelGiorno KEKathleen E , Lee HJHo-Joon , Purohit VVinee , Sagalovskiy IRIrina R , Ma AAlice , Kapilian JJonathan , Firl CEMChristina E M , Decker ARAmanda R , Sastra SASteve A , Palermo CFCarmine F , Andrade LRLeonardo R , Sajjakulnukit PPeter , Zhang LLi , Tolstyka ZPZachary P , Hirschhorn TTal , Lamb CCandice , Liu TTong , Gu WWei , Seeley ESE Scott , Stone EEverett , Georgiou GGeorge , Manor UUri , Iuga AAlina , Wahl GMGeoffrey M , Stockwell BRBrent R , Lyssiotis CACostas A , Olive KPKenneth P . Science (New York, N.Y.). 2020 4 3; 368(6486). 85-89

ABSTRACT

Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system x is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x subunit, , induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

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