biostudies-literatureViswanathan VSNCATS NIH HHSNIDDK NIH HHSHoward Hughes Medical InstituteNCI NIH HHSNIGMS NIH HHS453-457https://www.ebi.ac.uk/biostudies/studies/S-EPMC5667900biostudies-literatureUnknown547(7664)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 promoNatureDependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.PMC5667900R01 GM085081UL1 TR001102P30 CA008748R01 CA097061U01 CA168397K08 CA218420R35 CA209896R01 CA121941R01 CA129933R01 CA154480U24 CA194107U01 CA176058U01 CA217848R01 GM038627P50 CA092629R01 GM074024R01 CA208100R01 CA161061P30 DK043351R01 CA193837U01 CA176152U01 CA199253Kaffenberger SDViswanathan VSHuang CEaton JKStockwell BRRees MGHaber DATamayo PShamji AFDhruv HDBoehm JSShimada KGao DSeashore-Ludlow BLevesque MPGill SChattopadhyay SBoskovic ZVChen YViswanathan SRChen SAguirre AJEngelman JAWu XHahn WCHon CSBerens MEJavaid STseng YYRoider EMKotz JDRyan MJClemons PAWolpin BMSchreiber SLYang WSCleary JMDoench JGEichhoff OMMesirov JPfalseDependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.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 promo2017-01-01T00:00:00Z2017 Jul2026-04-16T07:15:46.86Z2019-03-26T23:47:50ZS-EPMC56679002867878510.1038/nature23007