Stabilized epithelial phenotype of cancer cells in primary tumors leads to increased colonization of liver metastasis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is therapeutically recalcitrant and metastatic. Partial epithelial to mesenchymal transition (EMT) is associated with metastasis; however, a causal connection needs further unraveling. Here, we use single-cell RNA sequencing and genetic mouse models to identify the functional roles of partial EMT and epithelial stabilization in PDAC growth and metastasis. A global EMT expression signature identifies ∼50 cancer cell clusters spanning the epithelial-mesenchymal continuum in both human and murine PDACs. The combined genetic suppression of Snail and Twist results in PDAC epithelial stabilization and increased liver metastasis. Genetic deletion of Zeb1 in PDAC cells also leads to liver metastasis associated with cancer cell epithelial stabilization. We demonstrate that epithelial stabilization leads to the enhanced collective migration of cancer cells and modulation of the immune microenvironment, which likely contribute to efficient liver colonization. Our study provides insights into the diverse mechanisms of metastasis in pancreatic cancer and potential therapeutic targets. [Display omitted] •Single-cell RNA-seq reveals a continuum of cancer epithelial-mesenchymal transition•Genetic deletion of both Snai1 and Twist1 or Zeb1 stabilizes epithelial phenotypes•Epithelial cancer cells have increased liver metastasis and collectively migrate•Mesenchymal-like cancer cells recruit fewer T cells The necessity of partial epithelial to mesenchymal transition for cancer metastasis is unclear. Applying single-cell RNA sequencing and genetic models to stabilize the epithelial phenotype, Carstens et al. show a continuum of epithelial and mesenchymal pancreatic cancer cells that use different mechanisms to migrate, escape the immune system, and metastasize.