Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of 'cancer stem cells (CSCs)' in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1+ tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1+ and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1+ cells in vivo, revealing the essential roles of Dclk1+ cells in expansion of pancreatic neoplasia in all progressive stages.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all human malignancies (Siegel et al, 2016)
This study clearly demonstrated for the first time the pivotal stem cell activity of Doublecortin-like kinase 1 (Dclk1)+ tumor cells for the maintenance and expansion of primary PDAC and its precursor lesions as well as metastatic lesions in vivo
We first investigated the proportion of Dclk1+ cells in pancreatic intraepithelial neoplasia (PanIN) and PDACs established in Pdx1-Flp; KrasFSF-G12D/+ (KF) and Pdx1-Flp; KrasFSF-G12D/+; Trp53frt/frt (KPF) mice, well-established mouse models of pancreatic tumors (Schonhuber et al, 2014)
Summary
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all human malignancies (Siegel et al, 2016). Cancer stem cells (CSCs) have been considered as a subpopulation of cancer cells capable of self-renewing and producing progeny cells that are critical for cancer growth (AlHajj et al, 2003; Bonnet and Dick, 1997; Lapidot et al, 1994) This mechanism may underlie the maintenance of cancer and its resistance to conventional therapies. Cancer Biology when the oncogenic Kras mutation is introduced together with inflammatory stimuli such as caerulein-induced pancreatitis in vivo (Westphalen et al, 2016) Another group showed a spheroid-forming capacity of acetylated tubulin+/DCLK1+ PDAC cells in vitro (Bailey et al, 2014). These reports demonstrate the potential of Dclk1+ cells to form pancreatic tumors under specific conditions, the stem cell dynamics in vivo within established tumors has not been explored. This study clearly demonstrated for the first time the pivotal stem cell activity of Dclk1+ tumor cells for the maintenance and expansion of primary PDAC and its precursor lesions as well as metastatic lesions in vivo
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