Abstract
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.
Highlights
The use of a-smooth muscle actin (aSMA)-Cre as a marker for partial Epithelial-to-mesenchymal transition (EMT) transgene reporter was motivated by our previous study, wherein lineage-tracing analyses of pancreatic ductal adenocarcinoma (PDAC) genetically engineered mouse models (GEMMs) with conditional loss of Snail or Twist revealed a significant loss of EMT program in tumors, as measured using immunolabeling for aSMA, Zeb1, Zeb2, and Slug (Zheng et al, 2015)
The fluorescence switch design ensures that cancer cells with a partial EMT program, once expressing aSMA, will remain tdTomato+/EGFPÀ even if/when they revert to epithelial morphology, possibly via mesenchymal-to-epithelial transition (MET)
This is in part due to the transient nature of the partial EMT phenotype of cancer cells and the challenges associated with employing fate mapping strategies (Mittal, 2018)
Summary
Previous studies have collectively offered evidence for the detection of EMT in circulating tumor cells (Rhim et al, 2012; Yu et al, 2013; Javaid et al, 2015) and conducted gain-of-function/loss-of-function assays targeting EMT-inducing transcription factors such as Twist, Snail, Slug, and Zeb (Guaita et al, 2002; Arumugam et al, 2009; Wellner et al, 2009; Taube et al, 2010; Tsai et al, 2012). These studies gave mechanistic insights into the molecular basis of EMT and linked the EMT program to metastasis.
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