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Nature DOI:10.1038/nature23007

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

Publication TypeJournal Article
Year of Publication2017
AuthorsViswanathan, VS, Ryan, MJ, Dhruv, HD, Gill, S, Eichhoff, OM, Seashore-Ludlow, B, Kaffenberger, SD, Eaton, JK, Shimada, K, Aguirre, AJ, Viswanathan, SR, Chattopadhyay, S, Tamayo, P, Yang, WSeok, Rees, MG, Chen, S, Bošković, ŽV, Javaid, S, Huang, C, Wu, X, Tseng, Y-Y, Roider, EM, Gao, D, Cleary, JM, Wolpin, BM, Mesirov, JP, Haber, DA, Engelman, JA, Boehm, JS, Kotz, JD, Hon, CS, Chen, Y, Hahn, WC, Levesque, MP, Doench, JG, Berens, ME, Shamji, AF, Clemons, PA, Stockwell, BR, Schreiber, SL
Date Published2017 07 27
KeywordsCadherins, 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, Prostatic Neoplasms, Proteomics, Proto-Oncogene Proteins B-raf, Reproducibility of Results, Zinc Finger E-box-Binding Homeobox 1

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.


Alternate JournalNature
PubMed ID28678785
PubMed Central IDPMC5667900
Grant ListR35 CA209896 / CA / NCI NIH HHS / United States
U01 CA176152 / CA / NCI NIH HHS / United States
R01 CA129933 / CA / NCI NIH HHS / United States
R01 CA193837 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
U24 CA194107 / CA / NCI NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA161061 / CA / NCI NIH HHS / United States
R01 GM085081 / GM / NIGMS NIH HHS / United States
U01 CA168397 / CA / NCI NIH HHS / United States
R01 CA097061 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
R01 CA154480 / CA / NCI NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States
U01 CA217848 / CA / NCI NIH HHS / United States