EMT and dissemination precede pancreatic tumor formation

By A. Rhim, Emily T Mirek, Nicole M. Aiello, A. Maitra, Jennifer M. Bailey, Florencia McCallister, Maximilian Reichert, G. Beatty, A. Rustgi, R. Vonderheide and 2 more. Cell, 2012

2,106 citations recorded by the source corpus.

Summary Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-tomesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide new insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.

Subfields: Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/cea406e10cd9d56eb08e86df1f709aaa6f593e75

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Citations in the corpus

EMT subtype influences epithelial plasticity and mode of cell migration (2018, background): “Mouse Strains—KrasLSL-G12D; p53L/+; Pdx1-cre; Rosa26YFP/YFP (KPCY) mice have been described previously (Rhim et al., 2012).”
Circulating tumor cells: liquid biopsy of cancer. (2013, background): “Interestingly, results with a mouse model showed that pancreatic cells with a mesenchymal phenotype and stem cell properties circulated in the blood and seeded the liver before any primary tumor was detectable (33).”
EMT, MET, plasticity and tumor metastasis (2020, methodology): “EMT is known to occur during mammalian development, wound healing, and cancer metastasis EpCAM (Epithelial cell adhesion molecule) a glycoprotein on the cellular membrane involved in cell-to-cell adhesion and multiple cell signaling pathways within epithelial cells.”
Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). (2014, background): “Advocates of neoadjuvant treatment suggest that these retrospective findings may arise from the effect of neoadjuvant treatment on occult microscopic metastases, which have been shown to occur prior to the formation of the primary tumor in mouse models.(45,46) Future randomized studies may provide e”
Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “Furthermore, several other potential sources of CAFs have been identified, such as epithelial cells [63, 64], pericytes [65], monocytes [66], endothelial cells [67] and smooth muscle cells [68].”
Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis (2015, background): “…various epithelial and mesenchymal markers are present in primary breast and ovarian cancer (15, 102), in multiple cell lines belonging to ovarian, lung, and renal cell carcinoma (64, 103, 104), as well as in mouse models of pancreatic ductal adenocarcinoma (PDAC) and prostate cancer (105, 106).”
Tumor-derived granulocyte-macrophage colony stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer (2012, background): “This approach led to sensitive (>95% of all pancreatic epithelial cells) and specific labeling of pancreas epithelial-derived cells, with no stromal cells labeled (Rhim et al., 2012).”
Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. (2012, background): “…tumor cells in distant organs in our spontaneous tumor model and in cancer patients, both our study and several clinical studies found that circulating tumor cells in the blood present many molecular features of EMT (Hou et al., 2011; Kallergi et al., 2011; Min et al., 2009; Rhim et al., 2012).”
Liquid Biopsy: From Discovery to Clinical Application. (2021, background): “Data obtained in mouse models (59) and patients with cancer (60, 61) indicate that blood-borne dissemination of cancer cells occurs early during tumor development, which provided the rationale to explore CTCs as marker for early detection of cancer.”