EMT sensitizes pancreatic cancer cells to NK cell killing in the liver

https://ibbme.utoronto.ca/event/emt-sensitizes-pancreatic-cancer-cells-to-nk-cell-killing-in-the-liver/ For metastasis to occur, cancer cells must leave the primary tumor, enter distant tissues, resume proliferation, and avoid elimination by the immune system. Studies from several cancers have shown that this sequence of steps can be accompanied by phenotypic transitions of the cancer cells. The dynamics of these changes and their impact on pancreatic cancer metastasis are, however, not well understood. To determine the phenotypic transitions of pancreatic cancer cells during metastasis, we investigated the metastatic behavior of cell lines derived from the KPC mouse model of pancreatic cancer (KrasLSL-G12D; Trp53R172H; Pdx1-Cre). Through intravital imaging of orthotopic pancreatic tumors, we observed that actively disseminating pancreatic cancer cells were single, elongated, slow-moving cells, consistent with epithelial to mesenchymal transition (EMT). We found that EMT, induced by transforming growth factor β (TGF-β) signaling, promotes single cell invasion in pancreatic cancer cells. We identified SNAIL and ZEB2 as the transcription factors responsible for driving EMT in our model. While EMT is well-known to promote invasion of cancer cells, the reverse process of mesenchymal-to-epithelial transition (MET) has been proposed to be an obligatory step before the cells can resume proliferation. To visualize EMT-MET plasticity in vivo we engineered a fluorescent reporter of EMT using CRISPR/Cas9 genome editing. With this strategy, we showed that at the secondary site, cells that had undergone EMT-mediated dissemination spontaneously transitioned back to the epithelial phenotype. To test the role of epithelial-mesenchymal plasticity in the colonization of the liver we enforced irreversible EMT by stably overexpressing SNAIL. Failure to initiate the second phenotypic switch -MET- curtailed metastasis, as mesenchymal, disseminated cancer cells were eliminated by the immune system in the liver, specifically by NK cells. Taken together, our data provide evidence of a link between epithelial-mesenchymal plasticity and anti-cancer immunity in pancreatic cancer metastasis. Importantly, we describe a critical role for NK cells in controlling pancreatic cancer metastasis in the liver