Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness1,2,3,4. 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 understood1,2,3,4,5,6. 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 peroxides7,8. 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 enzymes8,9. 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 death8. 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
We thank M. J. Hangauer, M. T. McManus, F. McCormick, K. Dutton-Regester, L. V. Kemeny, D. J. Adams and Y. Drier for valuable discussions and L. Hartman for execution of in vivo studies. This project has been supported by grants from the National Cancer Institute (Cancer Target Discovery and Development Network grant U01CA176152 to S.L.S., U01CA168397 to M.E.B., 5R01CA097061 and R01CA161061 to B.R.S., NCI-CA129933 to D.A.H., P30CA008748 to Y.C.), the National Institutes of Health (R01GM038627 to S.L.S., 5R01GM085081 to B.R.S.), the Swiss National Fund (310030_149946, to M.P.L.) and Howard Hughes Medical Institute (D.A.H., S.L.S.).
Extended data figures
This table contains mesenchymal scores for 516 carcinoma-derived cell lines calculated using single-sample gene set enrichment analysis from Taube, Goger and Byers EMT gene sets.
This table contains mesenchymal score-correlations for 481 compounds computed from AUCs across 491 carcinoma-derived cell lines listed in Supplementary Table 1.
This table contains gene-expression data for MCF-7 ER-Snail-1 cells (Haber Lab) treated with 4-hydroxytamoxifen (4-OHT) for 120 hours, allowed to recover from 4-OHT treatment for 24 hours, and then cultured in 384-well format in the absence of 4-OHT for 96 hours. These conditions model the compound exposure conditions for 4-OHT-induced MCF-7 ER-Snail-1 cells shown in Extended Data Fig. 6. Data are shown relative to ethanol-treated control cells.