@article{0195447ff94d479c9372b3ceb5653a8c,
title = "Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression",
abstract = "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.",
author = "Yee, {Patricia P.} and Yiju Wei and Kim, {Soo Yeon} and Tong Lu and Chih, {Stephen Y.} and Cynthia Lawson and Miaolu Tang and Zhijun Liu and Benjamin Anderson and Krishnamoorthy Thamburaj and Young, {Megan M.} and Aregawi, {Dawit G.} and Glantz, {Michael J.} and Zacharia, {Brad E.} and Specht, {Charles S.} and Wang, {Hong Gang} and Wei Li",
note = "Funding Information: We would like to thank Dr. Kun-liang Guan for reagents; members of the Li Laboratory for helpful discussions; Dr. Kristin Browning from the Department of Neural and Behavioral Sciences for equipment sharing; Ms. Kristin Shuler and Mr. John Graybeal from the Department of Neurosurgery{\textquoteright}s Neuroscience Research Institute for assistance with IRB submissions; Dr. Han Chen from the Transmission Electron Microscopy Core; Mr. Nate Sheaffer, Ms. Jade Vogel, and Mr. Joseph Bednarczyk from the Flow Cytometry Core; Dr. Thomas Abraham and Mr. Wade Edris from the Microscopy Imaging Core (Leica SP8 Confocal: 1S10OD010756-01A1 CB); Dr. Sang Lee from the Bioluminescent Imaging Core; Dr. Teodora Orendovici and Dr. Yuka Imamura from the Genomics Sciences Core; Dr. Katherine Aird from the shRNA library core; Ms. Gretchen Snavely and Ms. Erin Mattern from the Comparative Medicine Histopathology Core; Ms. Jessica Wingate from the Comparative Medicine Diagnostic Laboratory; Ms. Marianne Klinger from the Department of Pathology{\textquoteright}s Molecular and Histopathology Core at Penn State College of Medicine for technical support and biospecimen processing; and Dr. Christopher Yee for editorial assistance. We acknowledge support from the National Institutes of Neurological Disorders and Stroke (R01 NS109147 to W.L.), Meghan Rose Bradley Foundation (214389 to W.L.), American Cancer Society Institutional Research Grant (124171-IRG-13-043-01 to W.L.), the Four Diamonds Fund for Pediatric Cancer Research (to PSU), and Penn State College of Medicine Medical Scientist Training Program (5T32GM118294 to P.Y. through PSU). Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-19193-y",
language = "English (US)",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}