Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression.
Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression.
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DOI：
10.1038/s41467-020-19193-y
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发表时间：
2020-10-27
影响因子：
16.6
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Yee PP;Wei Y;Kim SY;Lu T;Chih SY;Lawson C;Tang M;Liu Z;Anderson B;Thamburaj K;Young MM;Aregawi DG;Glantz MJ;Zacharia BE;Specht CS;Wang HG;Li W
肿瘤坏死在许多癌症中普遍存在并预示着不良预后。尽管它被认为是由慢性缺血引起的，但驱动相关细胞死亡的根本性质和机制仍然不清楚。在这里，我们发现胶质母细胞瘤（GBM）的坏死涉及中性粒细胞触发的铁死亡。在具有 PDZ 结合基序驱动的 GBM 小鼠模型中，转录共激活子过度激活，中性粒细胞在时间和空间上与坏死一致。中性粒细胞耗竭可抑制坏死。从小鼠脑肿瘤中分离出的中性粒细胞杀死共培养的肿瘤细胞。从机制上讲，中性粒细胞通过将含有髓过氧化物酶的颗粒转移到肿瘤细胞中，诱导肿瘤细胞内铁依赖性脂质过氧化物的积累。髓过氧化物酶的抑制或耗竭可抑制中性粒细胞诱导的肿瘤细胞的细胞毒性。瘤内谷胱甘肽过氧化物酶 4 过度表达或酰基辅酶 A 合成酶长链家族成员 4 耗竭可减少肿瘤的坏死和侵袭性。此外，对人类 GBM 的分析支持中性粒细胞和铁死亡与坏死相关并预测生存率较差。因此，我们的研究将铁死亡确定为 GBM 坏死的根本性质，并揭示了铁死亡的促肿瘤作用。总之，我们提出，早期肿瘤进展（即缺血）期间发生的某些肿瘤损伤会将中性粒细胞募集到组织损伤部位，从而导致正反馈循环，从而最大程度地放大 GBM 坏死的发展。肿瘤坏死与胶质母细胞瘤患者的肿瘤侵袭性和不良预后相关，但其潜在机制仍知之甚少。在这里，作者表明，在胶质母细胞瘤的异种移植小鼠模型中，肿瘤浸润的中性粒细胞通过促进髓过氧化物酶诱导的肿瘤细胞铁死亡来放大坏死。
Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent. Tumour necrosis is associated with tumour aggressiveness and poor outcomes in patients with glioblastomas, but the underlying mechanisms remain poorly understood. Here, the authors show that in a xenograft mouse model of glioblastoma, tumour-infiltrating neutrophils amplify necrosis by promoting myeloperoxidase-induced tumour cell ferroptosis.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
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：
50.3
作者：
Granot Z;Henke E;Comen EA;King TA;Norton L;Benezra R
通讯作者：
Benezra R
DOI：
10.1073/pnas.77.5.2936
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
BREITMAN, TR;SELONICK, SE;COLLINS, SJ
通讯作者：
COLLINS, SJ
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M