Microenvironmental cues determine tumor cell susceptibility to neutrophil cytotoxicity

Maya Gershkovitz, Tanya Fainsod-Levi, Saleh Khawaled, Merav E. Shaul, Ronit V. Sionov, Leonor Cohen-Daniel, Rami I. Aqeilan, Yoav D. Shaul, Zvi G. Fridlender, Zvi Granot*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


We have recently shown that neutrophil antitumor cytotoxicity is Ca dependent and is mediated by TRPM2, an H2O2-dependent Ca channel. However, neutrophil antitumor activity is dependent on context and is manifested in the premetastatic niche, but not at the primary site. We therefore hypothesized that expression of TRPM2 and the consequent susceptibility to neutrophil cytotoxicity may be associated with the epithelial/mesenchymal cellular state. We found that TRPM2 expression was upregulated during epithelial-to-mesenchymal transition (EMT), and mesenchymal cells were more susceptible to neutrophil cytotoxicity. Conversely, cells undergoing mesenchymal-to-epithelial transition (MET) expressed reduced levels of TRPM2, rendering them resistant to neutrophil cytotoxicity. Cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. These data identify TRPM2 as the link between environmental cues at the primary tumor site, tumor cell susceptibility to neutrophil cytotoxicity, and disease progression. Furthermore, these data identify EMT as a process enhancing tumor-cell immune susceptibility and, by contrast, MET as a novel mode of immune evasion.

Original languageAmerican English
Pages (from-to)5050-5059
Number of pages10
JournalCancer Research
Issue number17
StatePublished - 1 Sep 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, 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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