Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression

Patricia P. Yee, Yiju Wei, Soo-Yeon Kim, Tong Lu, Stephen Y. Chih, Cynthia Lawson, Miaolu Tang, Zhijun Liu, Benjamin Anderson, Krishnamoorthy Thamburaj, Megan M. Young, Dawit G. Aregawi, Michael J. Glantz, Brad E. Zacharia, Charles S. Specht, Hong-Gang Wang and Wei Li ()
Additional contact information
Patricia P. Yee: Penn State College of Medicine
Yiju Wei: Penn State College of Medicine
Soo-Yeon Kim: Penn State College of Medicine
Tong Lu: Penn State College of Medicine
Stephen Y. Chih: Medical Scientist Training Program, Penn State College of Medicine
Cynthia Lawson: Penn State College of Medicine
Miaolu Tang: Penn State College of Medicine
Zhijun Liu: Penn State College of Medicine
Benjamin Anderson: Penn State College of Medicine
Krishnamoorthy Thamburaj: Penn State College of Medicine
Megan M. Young: Penn State College of Medicine
Dawit G. Aregawi: Penn State College of Medicine
Michael J. Glantz: Penn State College of Medicine
Brad E. Zacharia: Penn State College of Medicine
Charles S. Specht: Penn State College of Medicine
Hong-Gang Wang: Penn State College of Medicine
Wei Li: Penn State College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-22

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19193-y

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