TRPM2 mediates neutrophil killing of disseminated tumor cells

Neutrophils play a critical role in cancer, with both pro- and anti-tumor neutrophil subpopulations reported. The anti-tumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Since cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils employ to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H2O2. We report here that neutrophil cytotoxicity is Ca2+-dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca2+ 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.

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