Supplemental Figure S2. Circulating tumor cells express higher levels of TRPM2 compared with primary tumor cells in pancreatic cancer patients. A. Transcriptome analysis of mesenchymal genes, epithelial genes and TRPM2 on primary 4T1 tumor cells and circulating 4T1 tumor cells. The analysis was performed on dataset (GSE37244) published by LeBlue et al. (28). B. Microarray study for gene expression (GSE18670) changes in 6 samples from pancreatic cancer primary tumor (Primary) and circulating tumor cells (CTC) was described previously by Sergeant at al. (29). Here the same dataset was reanalyzed for the log2 expression ratio of TRMP2 in these samples. Data show TRPM2 expression in primary tumor cells (blue) and CTC (Red). *p<0.05 (2-tailed paired t-test).
ARTICLE ABSTRACT
We have recently shown that neutrophil antitumor cytotoxicity is Ca2+ dependent and is mediated by TRPM2, an H2O2-dependent Ca2+ 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.Significance: EMT is required for metastatic spread and concomitantly enhances tumor cell susceptibility to neutrophil cytotoxicity. Cancer Res; 78(17); 5050–9. ©2018 AACR.
