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Dclk1 distinguishes between tumor and normal stem cells in the intestine

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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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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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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Supplementary Figures 1–16 and Supplementary Table 1 (PDF 3157 kb)

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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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