Author
Listed:
- Patricia P. Yee
(Penn State College of Medicine
Medical Scientist Training Program, 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
Penn State College of Medicine)
- Dawit G. Aregawi
(Penn State College of Medicine
Penn State Cancer Institute, Penn State College of Medicine
Penn State College of Medicine)
- Michael J. Glantz
(Penn State College of Medicine
Penn State Cancer Institute, Penn State College of Medicine
Penn State College of Medicine)
- Brad E. Zacharia
(Penn State College of Medicine
Penn State Cancer Institute, Penn State College of Medicine
Penn State College of Medicine)
- Charles S. Specht
(Penn State College of Medicine
Penn State College of Medicine
Penn State College of Medicine)
- Hong-Gang Wang
(Penn State College of Medicine
Penn State College of Medicine)
- Wei Li
(Penn State College of Medicine
Penn State College of Medicine)
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.
Suggested Citation
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 & M, 2020.
"Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression,"
Nature Communications, Nature, vol. 11(1), pages 1-22, December.
Handle:
RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19193-y
DOI: 10.1038/s41467-020-19193-y
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Cited by:
- Marco Luciani & Chiara Garsia & Stefano Beretta & Ingrid Cifola & Clelia Peano & Ivan Merelli & Luca Petiti & Annarita Miccio & Vasco Meneghini & Angela Gritti, 2024.
"Human iPSC-derived neural stem cells displaying radial glia signature exhibit long-term safety in mice,"
Nature Communications, Nature, vol. 15(1), pages 1-24, December.
- Zhihong Chen & Nishant Soni & Gonzalo Pinero & Bruno Giotti & Devon J. Eddins & Katherine E. Lindblad & James L. Ross & Montserrat Puigdelloses Vallcorba & Tanvi Joshi & Angelo Angione & Wes Thomason , 2023.
"Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma,"
Nature Communications, Nature, vol. 14(1), pages 1-24, December.
- Yun Chang & Xuechao Cai & Ramizah Syahirah & Yuxing Yao & Yang Xu & Gyuhyung Jin & Vijesh J. Bhute & Sandra Torregrosa-Allen & Bennett D. Elzey & You-Yeon Won & Qing Deng & Xiaojun Lance Lian & Xiaogu, 2023.
"CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy,"
Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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