Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging
- Kyoto University Graduate School of Medicine, Japan
- Klinikum rechts der Isar Technische Universität München, Germany
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.
Data availability
Microarray data have been deposited in GEO under accession codes GSE139167.
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Gene expression profiles of Dclk1+ and Dclk1- PDAC cellsNCBI Gene Expression Omnibus, GSE139167.
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Expression data from Mayo Clinic Pancreatic Tumor and Normal samplesNCBI Gene Expression Omnibus, GSE16515.
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Integrative Survival-Based Molecular Profiling of Human Pancreatic CancerNCBI Gene Expression Omnibus, GSE32676.
Article and author information
Author details
Funding
Grants-in-Aid KAKENHI (26293173)
- Hiroshi Seno
Naito Foundation (N/A)
- Hiroshi Seno
Princess Takamatsu Cancer Research Fund (13-24514)
- Tsutomu Chiba
Princess Takamatsu Cancer Research Fund (17-24924)
- Hiroshi Seno
Takeda Science Foundation (201749741)
- Hiroshi Seno
Uehara Memorial Foundation (201720143)
- Hiroshi Seno
Mochida Foundation (201356)
- Tsutomu Chiba
Mochida Foundation (2017bvAg)
- Hiroshi Seno
Mitsubishi Foudation (281119)
- Hiroshi Seno
Mitsubishi Foudation (201910037)
- Hiroshi Seno
European Research Council (648521)
- Dieter Saur
Grants-in-Aid KAKENHI (15H06334)
- Takahisa Maruno
Deutsche Forschungsgemeinschaft (1374/4-2)
- Dieter Saur
Grants-in-Aid KAKENHI (16K09394)
- Akihisa Fukuda
Grants-in-Aid KAKENHI (16K15427)
- Hiroshi Seno
Grants-in-Aid KAKENHI (17H04157)
- Hiroshi Seno
Grants-in-Aid KAKENHI (19H03639)
- Akihisa Fukuda
apan Agency for Medical Research and Development (19cm0106142h0002)
- Hiroshi Seno
apan Agency for Medical Research and Development (19cm6010022h0002)
- Akihisa Fukuda
Kobayashi Foundation for Cancer Research (N/A)
- Hiroshi Seno
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kay F Macleod, University of Chicago, United States
Ethics
Animal experimentation: All animal experiments were approved by the animal research committee of the Kyoto University and performed in accordance with Japanese government regulations. All surgery was performed under Isoflurane anesthesia, and every effort was made to minimize suffering.
Human subjects: Surgically resected specimens of pancreatic cancer tissues were obtained from patients who had been admitted to Kyoto University Hospital. Written informed consent was obtained from all patients and study protocol (#G1200-1) was approved by Ethics Committee of Kyoto University Hospital.
Version history
- Received: January 13, 2020
- Accepted: November 24, 2020
- Accepted Manuscript published: January 4, 2021 (version 1)
- Version of Record published: January 11, 2021 (version 2)
Copyright
© 2021, Maruno et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging
eLife 10:e55117.
https://doi.org/10.7554/eLife.55117
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