Dual reporter genetic mouse models of pancreatic cancer identify an epithelial‐to‐mesenchymal transition‐independent metastasis program

Epithelial‐to‐mesenchymal transition (EMT) is a recognized eukaryotic cell differentiation program that is also observed in association with invasive tumors. Partial EMT program in carcinomas imparts cancer cells with mesenchymal‐like features and is proposed as essential for metastasis. Precise determination of the frequency of partial EMT program in cancer cells in tumors and its functional role in metastases needs unraveling. Here, we employed mesenchymal cell reporter mice driven by αSMA‐Cre and Fsp1‐Cre with genetically engineered mice that develop spontaneous pancreatic ductal adenocarcinoma (PDAC) to monitor partial EMT program. Both αSMA ‐ and Fsp1 ‐ Cre ‐mediated partial EMT programs were observed in the primary tumors. The established metastases were primarily composed of cancer cells without evidence for a partial EMT program, as assessed by our fate mapping approach. In contrast, metastatic cancer cells exhibiting a partial EMT program were restricted to isolated single cancer cells or micrometastases (3–5 cancer cells). Collectively, our studies identify large metastatic nodules with preserved epithelial phenotype and potentially unravel a novel metastasis program in PDAC. Synopsis Epithelial‐to‐mesenchymal transition (EMT) is considered essential for pancreatic cancer metastasis. This study identifies non‐EMT‐mediated metastasis by lineage tracing partial EMT via a dual‐recombinase system in mice with fluorescence‐switching reporters and mesenchymal fate mapping transgenes. Partial EMT programs were observed in 2–3% cancer cells of the primary PDAC tumors, as captured by the lineage‐tracing system. Established lung and liver metastases were composed of cancer cells without evidence for partial EMT program, as determined by the acquisition of mesenchymal markers such as αSMA, FSP1 or vimentin. Metastatic cancer cells exhibiting a partial EMT program were observed only as disseminated single cancer cells or micrometastases (3–5 cells), but did not grow to become large secondary tumors. Graphical Abstract Epithelial‐to‐mesenchymal transition (EMT) is considered essential for pancreatic cancer metastasis. This study identifies non‐EMT‐mediated metastasis by lineage tracing partial EMT via a dual‐recombinase system in mice with fluorescence‐switching reporters and mesenchymal fate mapping transgenes.