Cysteine depletion induces pancreatic tumor ferroptosis in mice

Michael A Badgley; Daniel M Kremer; H Carlo Maurer; Kathleen E DelGiorno; Ho-Joon Lee; Vinee Purohit; Irina R Sagalovskiy; Alice Ma; Jonathan Kapilian; 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

doi:10.1126/science.aaw9872

Cysteine depletion induces pancreatic tumor ferroptosis in mice

Science. 2020 Apr 3;368(6486):85-89. doi: 10.1126/science.aaw9872.

Authors

Michael A Badgley^{1

2}, Daniel M Kremer^{3

4}, H Carlo Maurer^{1

2

5}, Kathleen E DelGiorno⁶, Ho-Joon Lee^{3

4}, Vinee Purohit^{3

4}, Irina R Sagalovskiy^{1

2}, Alice Ma^{1

2}, Jonathan Kapilian^{1

2}, Christina E M Firl^{1

2}, Amanda R Decker^{1

2}, Steve A Sastra^{1

2}, Carmine F Palermo^{1

2}, Leonardo R Andrade⁷, Peter Sajjakulnukit^{3

4}, Li Zhang^{4

8}, Zachary P Tolstyka^{3

4}, Tal Hirschhorn⁹, Candice Lamb¹⁰, Tong Liu^{2

11

12}, Wei Gu^{2

11

12}, E Scott Seeley^{13

14}, Everett Stone^{10

15}, George Georgiou¹⁵, Uri Manor⁷, Alina Iuga^{2

12}, Geoffrey M Wahl⁶, Brent R Stockwell⁹, Costas A Lyssiotis^{3

4

16}, Kenneth P Olive^{17

2}

Affiliations

¹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
² Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
³ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Klinikum rechts der Isar, II, Medizinische Klinik, Technische Universität München, 81675, Munich, Germany.
⁶ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁷ Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁸ Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48105, USA.
⁹ Departments of Biological Sciences and Chemistry, Columbia University, New York, NY 10027, USA.
¹⁰ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
¹¹ Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
¹² Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA.
¹³ Department of Pathology, University of California, San Francisco, CA 94143, USA.
¹⁴ Salvo Therapeutics, San Francisco, CA 94117, USA.
¹⁵ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
¹⁶ Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁷ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. kenolive@columbia.edu.

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_C ^- 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_C ^- subunit, Slc7a11, 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Pancreatic Ductal / metabolism*
Carcinoma, Pancreatic Ductal / pathology*
Cationic Amino Acid Transporter 1 / genetics
Cell Line, Tumor
Cystathionine gamma-Lyase / administration & dosage
Cystathionine gamma-Lyase / pharmacology
Cysteine / deficiency*
Cystine / metabolism
Ferroptosis* / drug effects
Ferroptosis* / genetics
Gene Deletion
Humans
Mice
Mice, Mutant Strains
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology*

Substances

Cationic Amino Acid Transporter 1
Slc7a1 protein, mouse
Cystine
Cystathionine gamma-Lyase
Cysteine

Abstract

Publication types

MeSH terms

Substances

Grants and funding