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Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

  • Viswanathan VS Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Ryan MJ Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Dhruv HD Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA.
  • Gill S Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Eichhoff OM Department of Dermatology, University of Zurich, University Hospital of Zurich, Wagistrasse 14, CH-8952, Schlieren, Zürich, Switzerland.
  • Seashore-Ludlow B Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Kaffenberger SD Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • Eaton JK Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Shimada K Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
  • Aguirre AJ Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Viswanathan SR Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Chattopadhyay S Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Tamayo P Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Yang WS Department of Biological Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, USA.
  • Rees MG Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Chen S Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Boskovic ZV Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Javaid S Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, Massachusetts 02129, USA.
  • Huang C Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Wu X Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Tseng YY Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Roider EM Department of Dermatology, University of Zurich, University Hospital of Zurich, Wagistrasse 14, CH-8952, Schlieren, Zürich, Switzerland.
  • Gao D Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • Cleary JM Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  • Wolpin BM Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  • Mesirov JP Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Haber DA Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, Massachusetts 02129, USA.
  • Engelman JA Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
  • Boehm JS Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Kotz JD Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Hon CS Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Chen Y Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • Hahn WC Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Levesque MP Department of Dermatology, University of Zurich, University Hospital of Zurich, Wagistrasse 14, CH-8952, Schlieren, Zürich, Switzerland.
  • Doench JG Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Berens ME Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA.
  • Shamji AF Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Clemons PA Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • Stockwell BR Department of Biological Sciences, Department of Chemistry, Columbia University, 550 West 120th Street, New York, New York 10027, USA.
  • Schreiber SL Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
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  • 2017-07-06
Published in:
  • Nature. - 2017
Cadherins
Cell Death
Cell Line, Tumor
Cell Lineage
Cell Transdifferentiation
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
Glutathione Peroxidase
Humans
Iron
Lipid Peroxidation
Lipid Peroxides
Male
Melanoma
Mesoderm
Neoplasms
Phospholipid Hydroperoxide Glutathione Peroxidase
Prostatic Neoplasms
Proteomics
Proto-Oncogene Proteins B-raf
Reproducibility of Results
Zinc Finger E-box-Binding Homeobox 1
English Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
Language
  • English
Open access status
green
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Persistent URL
https://folia.unifr.ch/global/documents/90962
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