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Dclk1 distinguishes between tumor and normal stem cells in the intestine

Nature Genetics volume 45, pages 98–103 (2013)Cite this article

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Abstract

There is great interest in tumor stem cells (TSCs) as potential therapeutic targets; however, cancer therapies targeting TSCs are limited. A drawback is that TSC markers are often shared by normal stem cells (NSCs)1,2,3,4; thus, therapies that target these markers may cause severe injury to normal tissues. To identify a potential TSC-specific marker, we focused on doublecortin-like kinase 1 (Dclk1). Dclk1 was reported as a candidate NSC marker in the gut5,6, but recent reports have implicated it as a marker of differentiated cells (for example, Tuft cells)7,8. Using lineage-tracing experiments, we show here that Dclk1 does not mark NSCs in the intestine but instead marks TSCs that continuously produce tumor progeny in the polyps of ApcMin/+ mice. Specific ablation of Dclk1-positive TSCs resulted in a marked regression of polyps without apparent damage to the normal intestine. Our data suggest the potential for developing a therapy for colorectal cancer based on targeting Dclk1-positive TSCs.

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Figure 1: Dclk1 marks postmitotic cells rather than NSCs in the intestine.
Figure 2: Dclk1 marks TSCs in the polyps of ApcMin/+ mice.
Figure 3: Dclk1+Lgr5+ tumor cells are observed at the base of intestinal polyps.
Figure 4: Dclk1+Lgr5+ cells have characteristics of TSCs in intestinal polyps.
Figure 5: Ablation of TSCs marked by Dclk1 results in tumor regression without substantial damage to normal intestine.
Figure 6: Dclk1 is a marker for TSCs rather than NSCs in the intestine.

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References

  1. Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 104, 10158–10163 (2007).

    Article  CAS  Google Scholar 

  2. O'Brien, C.A., Pollett, A., Gallinger, S. & Dick, J.E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).

    Article  CAS  Google Scholar 

  3. Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603–607 (2009).

    Article  CAS  Google Scholar 

  4. Todaro, M., Francipane, M.G., Medema, J.P. & Stassi, G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology 138, 2151–2162 (2010).

    Article  CAS  Google Scholar 

  5. Giannakis, M. et al. Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J. Biol. Chem. 281, 11292–11300 (2006).

    Article  CAS  Google Scholar 

  6. May, R. et al. Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26, 630–637 (2008).

    Article  Google Scholar 

  7. Gerbe, F., Brulin, B., Makrini, L., Legraverend, C. & Jay, P. DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology 137, 2179–2180 (2009).

    Article  CAS  Google Scholar 

  8. Saqui-Salces, M. et al. Gastric tuft cells express DCLK1 and are expanded in hyperplasia. Histochem. Cell Biol. 136, 191–204 (2011).

    Article  CAS  Google Scholar 

  9. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  Google Scholar 

  10. Sangiorgi, E. & Capecchi, M.R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).

    Article  CAS  Google Scholar 

  11. Bonnet, D. & Dick, J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).

    Article  CAS  Google Scholar 

  12. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. & Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  Google Scholar 

  13. Singh, S.K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).

    CAS  PubMed  Google Scholar 

  14. Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).

    Article  CAS  Google Scholar 

  15. Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).

    Article  CAS  Google Scholar 

  16. Cocciadiferro, L. et al. Profiling cancer stem cells in androgen-responsive and refractory human prostate tumor cell lines. Ann. NY Acad. Sci. 1155, 257–262 (2009).

    Article  CAS  Google Scholar 

  17. Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).

    Article  CAS  Google Scholar 

  18. Davies, E.J., Marsh, V. & Clarke, A.R. Origin and maintenance of the intestinal cancer stem cell. Mol. Carcinog. 50, 254–263 (2011).

    Article  CAS  Google Scholar 

  19. May, R. et al. Doublecortin and CaM kinase-like-1 and leucine-rich-repeat–containing G-protein–coupled receptor mark quiescent and cycling intestinal stem cells, respectively. Stem Cells 27, 2571–2579 (2009).

    Article  CAS  Google Scholar 

  20. Gerbe, F. et al. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J. Cell Biol. 192, 767–780 (2011).

    Article  CAS  Google Scholar 

  21. Koizumi, H., Tanaka, T. & Gleeson, J.G. Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration. Neuron 49, 55–66 (2006).

    Article  CAS  Google Scholar 

  22. Sauer, B. & Henderson, N. Targeted insertion of exogenous DNA into the eukaryotic genome by the Cre recombinase. New Biol. 2, 441–449 (1990).

    CAS  PubMed  Google Scholar 

  23. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  Google Scholar 

  24. Vermeulen, L. et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl. Acad. Sci. USA 105, 13427–13432 (2008).

    Article  CAS  Google Scholar 

  25. Verissimo, C.S. et al. Silencing of the microtubule-associated proteins doublecortin-like and doublecortin-like kinase-long induces apoptosis in neuroblastoma cells. Endocr. Relat. Cancer 17, 399–414 (2010).

    Article  CAS  Google Scholar 

  26. Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO J. 18, 5931–5942 (1999).

    Article  CAS  Google Scholar 

  27. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    Article  CAS  Google Scholar 

  28. Visvader, J.E. & Lindeman, G.J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755–768 (2008).

    Article  CAS  Google Scholar 

  29. Graham, S.M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).

    Article  CAS  Google Scholar 

  30. Saito, M. et al. Diphtheria toxin receptor–mediated conditional and targeted cell ablation in transgenic mice. Nat. Biotechnol. 19, 746–750 (2001).

    Article  CAS  Google Scholar 

  31. Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).

    Article  CAS  Google Scholar 

  32. Merlos-Suárez, A. et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8, 511–524 (2011).

    Article  Google Scholar 

Download references

Acknowledgements

We thank K. Kohno (Nara Institute of Science and Technology) for kindly providing diphtheria toxin. We also thank Y. Kimura, S. Ishizu, M. Nakatsuji, R. Akitake-Kawano, K. Furuyama and T.S. Stappenbeck for technical assistance and helpful suggestions. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI 10J02434, 21229009, 23590937, 24229005, 24659363, 24590914 and 24590916; the Research Program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Health and Labour Sciences Research Grants for Research on Intractable Diseases, Hepatitis, and Innovative Development and Practical Application of New Drugs for Hepatitis B from the Ministry of Health, Labour and Welfare, Japan; the Funding Program for Next-Generation World-leading Researchers (LS075) and Grants-in Aid from the Ministry of Education, Culture, Science, Sports and Technology of Japan; and the Princess Takamatsu Cancer Research Fund 10-24212.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yuki Nakanishi, Hiroshi Seno, Taro Ueo, Yuichi Yamaga, Takahisa Maruno, Naoko Nakanishi, Keitaro Kanda, Hideyuki Komekado, Mayumi Kawada & Tsutomu Chiba

  2. Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

    Ayumi Fukuoka & Shin Yonehara

  3. Institute for Virus Research, Kyoto University, Kyoto, Japan

    Akihiro Isomura & Ryoichiro Kageyama

  4. Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Kenji Kawada & Yoshiharu Sakai

  5. Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Motoko Yanagita

  6. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

    Yoshiya Kawaguchi

  7. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Makoto M Taketo

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  1. Yuki Nakanishi
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Contributions

Y.N. and H.S. designed the study. Y.N., H.S., A.F., T.U., T.M., N.N. and K. Kanda performed the experiments. Y.N., H.S. and A.I. analyzed the data. Y.N., H.S., Y.K. and T.C. prepared the manuscript with input from the other authors. K. Kawada, Y.S., M.Y. and M.M.T. provided essential materials. Y.Y., H.K. and M.K. provided technical support and discussion. M.Y., R.K., Y.K., M.M.T., S.Y. and T.C. supervised the project.

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Correspondence to Hiroshi Seno.

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The authors declare no competing financial interests.

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Nakanishi, Y., Seno, H., Fukuoka, A. et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet 45, 98–103 (2013). https://doi.org/10.1038/ng.2481

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