Dclk1 distinguishes between tumor and normal stem cells in the intestine

Nat Genet. 2013 Jan;45(1):98-103. doi: 10.1038/ng.2481. Epub 2012 Dec 2.

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); 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 gut, but recent reports have implicated it as a marker of differentiated cells (for example, Tuft cells). 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 Apc(Min/+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Order
  • Intestinal Mucosa / metabolism*
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / pathology
  • Intestinal Polyps / genetics
  • Intestinal Polyps / metabolism
  • Intestinal Polyps / pathology
  • Intestines / pathology
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Neoplastic Stem Cells / metabolism*
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Stem Cells / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • DCLK1 protein, human
  • Protein-Serine-Threonine Kinases