Year: 2019
Type: preprint
Abstract: Pancreatic ductal adenocarcinoma (PDA) is the third-leading cause of cancer mortality in the US and is highly resistant to classical, targeted, and immune therapies. We show that human PDA cells are dependent on the provision of exogenous cystine to avert a catastrophic accumulation of lipid reactive oxygen species (ROS) that, left unchecked, leads to ferroptotic cell death, both in vitro and in vivo . Using a dual-recombinase genetically engineered model, we found that acute deletion of Slc7a11 led to tumor-selective ferroptosis, tumor stabilizations/regressions, and extended overall survival. The mechanism of ferroptosis induction in PDA cells required the concerted depletion of both glutathione and coenzyme A, highlighting a novel branch of ferroptosis-relevant metabolism. Finally, we found that cystine depletion in vivo using the pre-IND agent cyst(e)inase phenocopied Slc7a11 deletion, inducing tumor-selective ferroptosis and disease stabilizations/regressions in the well-validated KPC model of PDA. One Sentence Summary Genetic and pharmacological targeting of cystine import induces pancreatic cancer-selective ferroptosis in vivo .
DOI: 10.1101/827972
Authors: Michael A. Badgley, Daniel Kremer, H. Carlo Maurer, Kathleen E. DelGiorno, Ho-Joon Lee, Vinee Purohit, Irina Sagalovskiy, Alice Ma, Jonathan Kapillian, Christina E.M. Firl, Amanda R. Decker, Steve A. Sastra, Carmine F. Palermo, Leonardo R. Andrade, Peter Sajjakulnukit, Li Zhang, Zachary P. Tolstyka, Tal Hirschhorn, Candice Lamb, Tong Liu, Wei Gu, E. Scott Seeley, Everett Stone, George Georgiou, Uri Manor, Alina Iuga, Geoffrey M. Wahl, Brent R. Stockwell, Costas A. Lyssiotis, Kenneth P. Olive
Institutions: Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, Columbia University, University of Michigan, Salk Institute for Biological Studies, U-M Rogel Cancer Center, The University of Texas at Austin, University of California, San Francisco, Michigan Medicine
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2986498620