Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging
Takahisa Maruno, Akihisa Fukuda, Norihiro Goto, Motoyuki Tsuda, Kozo Ikuta, Yukiko Hiramatsu, Satoshi Ogawa, Yuki Nakanishi, Yuichi Yamaga, Takuto Yoshioka, Kyoichi Takaori, Shinji Üemoto, Dieter Saur, Tsutomu Chiba, Hiroshi Seno
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.