TRPM2 mediates neutrophil killing of disseminated tumor cells

Maya Gershkovitz, Yaki Caspi, Tanya Fainsod-Levi, Ben Katz, Janna Michaeli, Saleh Khawaled, Shaya Lev, Lola Polyansky, Merav E. Shaul, Ronit V. Sionov, Leonor Cohen-Daniel, Rami I. Aqeilan, Yoav D. Shaul, Yasuo Mori, Rotem Karni, Zvi G. Fridlender, Alexander M. Binshtok, Zvi Granot*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H2O2. We report here that neutrophil cytotoxicity is Ca dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca channel. Perturbing TRPM2 expression limited tumor cell proliferation, leading to attenuated tumor growth. Concomitantly, cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. Significance: These findings identify the mechanism utilized by neutrophils to kill disseminated tumor cells and to limit metastatic spread.

Original languageAmerican English
Pages (from-to)2680-2690
Number of pages11
JournalCancer Research
Issue number10
StatePublished - 15 May 2018

Bibliographical note

Funding Information:
Z. Granot was supported by grants from the I-CORE Gene Regulation in Complex Human Disease, Center no. 41/11, the Israel Science Foundation (ISF), the Israel Cancer Research Foundation (RCDA), The Rosetrees Trust, the Lejwa Foundation, and the Israel Cancer Association.

Publisher Copyright:
© 2018 American Association for Cancer Research.


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