Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging.
Takahisa MarunoAkihisa FukudaNorihiro GotoMotoyuki TsudaKozo IkutaYukiko HiramatsuSatoshi OgawaYuki NakanishiYuichi YamagaTakuto YoshiokaKyoichi TakaoriShinji UemotoDieter SaurTsutomu ChibaHiroshi SenoPublished in: eLife (2021)
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.
Keyphrases
- stem cells
- induced apoptosis
- cell cycle arrest
- epithelial mesenchymal transition
- high grade
- cancer stem cells
- squamous cell carcinoma
- small cell lung cancer
- multiple sclerosis
- signaling pathway
- cell death
- oxidative stress
- cell proliferation
- mass spectrometry
- copy number
- pi k akt
- tyrosine kinase
- transforming growth factor
- cell therapy
- induced pluripotent stem cells
- protein kinase