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); 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.

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

“…Xenotransplantation studies in which cell populations were selected based upon (surface) marker expression, revealed LGR5+, CD133 (AC133 epitope), CD44 or CD166 as CSC markers (4,(13)(14)(15)(16)(17)(18)(19). These findings were supported with lineage tracing experiments in genetically defined mouse models (8,(20)(21)(22). However, these studies do not functionally test stem cells in established human cancers.…”

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…Doublecortin-like kinase 1 was originally described as a marker that was able to distinguish between Dclk1-positive tumor stem cells and Dclk1-negative normal stem cells in the intestine. 74 Later studies confirmed that Dclk1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms, and its expression marks a morphologically distinct subpopulation of cells with stem cells properties in pancreatic cancer. 75,76 In this scenario, it is tempting to suggest that chronic adaptation to metformin accelerates the retrogression from a differentiated cancer cell state to a more stem-like state endowed with enhanced migratory capacities (i.e., the "migrating cancer stem cells" concept originally proposed by Thomas Brabletz).…”

Gene expression signatures for identifying diffuse-type gastric cancer associated with epithelial-mesenchymal transition

“…In terms of other stem cell markers, a recent report suggested that Lgr5 + cells in mouse intestinal adenomas acquired the ability for cancerous growth as a stem cell (27). Dclk1 (doublecortin-like kinase 1), which is a candidate marker for intestinal cancer stem cells, did not dramatically differ in expression between diffuse-type GC and MSCs (28).…”