Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.
Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.
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DOI：
10.1038/nature23007
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发表时间：
2017-07-27
期刊：
影响因子：
64.8
通讯作者：
Schreiber SL
中科院分区：
文献类型：
--
作者：
Viswanathan 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 WS;Rees MG;Chen S;Boskovic ZV;Javaid S;Huang C;Wu X;Tseng YY;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
已经提出细胞状态的可塑性驱动对多种癌症疗法的抗性，从而限制其有效性。在人类肿瘤和癌细胞系中观察到的高间充质细胞状态与对不同癌症谱系的多种治疗方式的抗性有关，但这种状态的机制基础仍然不完全清楚。在这里，我们从分子上表征了人类癌细胞系和类器官中这种耐治疗的高间充质细胞状态，并表明它依赖于一种可药物化的脂质过氧化物酶途径，该途径可以防止铁凋亡，这是一种由有毒脂质过氧化物的积累诱导的非凋亡形式的细胞死亡。我们表明，这种细胞状态的特点是活性的酶，促进多不饱和脂质的合成。这些脂质是脂氧合酶进行脂质过氧化的底物。这种脂质代谢产生了对聚集在磷脂谷胱甘肽过氧化物酶（GPX 4）上的途径的依赖性，GPX 4是一种含硒代半胱氨酸的酶，其消散脂质过氧化物，从而防止铁介导的过氧化物反应，该过氧化物反应诱导铁凋亡细胞死亡。发现依赖于GPX 4存在于以ZEB 1高表达为特征的多种治疗抗性状态中，包括上皮来源的癌中的上皮-间充质转化、黑素瘤中的TGFβ介导的治疗抗性、前列腺癌中的治疗诱导的神经内分泌转分化和肉瘤，其由于其细胞来源而固定在间充质状态。我们发现，在不同的间充质细胞状态背景下，抑制脂质过氧化物酶途径诱导的铁光细胞死亡是治疗抗性癌细胞的一个特征。
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 nonapoptotic 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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4
作者：
Dixon SJ;Winter GE;Musavi LS;Lee ED;Snijder B;Rebsamen M;Superti-Furga G;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1126/science.aad0501
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tirosh I;Izar B;Prakadan SM;Wadsworth MH 2nd;Treacy D;Trombetta JJ;Rotem A;Rodman C;Lian C;Murphy G;Fallahi-Sichani M;Dutton-Regester K;Lin JR;Cohen O;Shah P;Lu D;Genshaft AS;Hughes TK;Ziegler CG;Kazer SW;Gaillard A;Kolb KE;Villani AC;Johannessen CM;Andreev AY;Van Allen EM;Bertagnolli M;Sorger PK;Sullivan RJ;Flaherty KT;Frederick DT;Jané-Valbuena J;Yoon CH;Rozenblatt-Rosen O;Shalek AK;Regev A;Garraway LA
通讯作者：
Garraway LA
影响因子：
--
作者：
Dančík V;Carrel H;Bodycombe NE;Seiler KP;Fomina-Yadlin D;Kubicek ST;Hartwell K;Shamji AF;Wagner BK;Clemons PA
通讯作者：
Clemons PA
影响因子：
64.5
作者：
Gao D;Vela I;Sboner A;Iaquinta PJ;Karthaus WR;Gopalan A;Dowling C;Wanjala JN;Undvall EA;Arora VK;Wongvipat J;Kossai M;Ramazanoglu S;Barboza LP;Di W;Cao Z;Zhang QF;Sirota I;Ran L;MacDonald TY;Beltran H;Mosquera JM;Touijer KA;Scardino PT;Laudone VP;Curtis KR;Rathkopf DE;Morris MJ;Danila DC;Slovin SF;Solomon SB;Eastham JA;Chi P;Carver B;Rubin MA;Scher HI;Clevers H;Sawyers CL;Chen Y
通讯作者：
Chen Y