Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem–like Cells Marked by DCLK1 Kinase

Abstract

DCLK1 is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem-like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a microRNA signature as a surrogate biomarker for DCLK1 in cancer stem-like cells. Utilizing RNA/miRNA sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic and stomach cancers. Notably, Cox regression and Kaplan-Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem-like cells in these malignancies.

Alternative splice variants of DCLK1 mark cancer stem cells, promote self‐renewal and drug‐resistance, and can be targeted to inhibit tumorigenesis in kidney cancer

“…DCLK1 is prognostic in colorectal, head and neck, lung and other cancers . To determine if DCLK1 is prognostic in RCC we performed Cox regression and Kaplan–Meier survival analyses.…”

“…However, despite significant differences in recurrence‐free survival (RFS) associated with total DCLK1 gene expression, Cox regression analysis of overall survival demonstrated no significant difference (Supporting Information Table II). Given these somewhat confounding results, and our previous hypothesis that DCLK1 expression may be more significant in early cancer before the DCLK1+ cell's progeny dilute its signal, we assessed clinical subgroups. In this context, DCLK1 Isoforms 2 or 4 were able to predict reduced OS in patients with low‐grade disease ( p < 0.05).…”

Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications

“…Thus, unlike humans, the 5'promoter of mDclk1 gene does not get hypermethylated and silenced during colon carcinogenesis in response to carcinogens or loss of APC function (34)(35)(36). In recent publications, however, this important difference in the isoform(s) being expressed by colonic tumors in humans vs. mouse models has been ignored (36,40), requiring re-evaluation of results reported in these and other articles, published previously. The various mouse and human isoforms of DCLK1 have been given many different names in literature, leading to much confusion in this field, as discussed (9).…”

“…Since then, 5'promoter of hDCLK1 gene has been reported to be hypermethylated in gastric (38), pancreatic (38), and lung cancers (39). Interpretation of data in light of these important discoveries, has however remained ignored by some investigators, who have published since 2014 in this field (36,40). A link to our comments, regarding inaccurate interpretation of some data published by Westphalen et al (36), is available at http://www.cell.com/cell-stem-cell/ comments/S1934-5909(16)30003-0.…”

Doublecotin-like kinase 1 increases chemoresistance of colorectal cancer cells through the anti-apoptosis pathway

“…Up-regulated expression of DCLK1 was found broadly in solid tumors almost all over the body, including the esophageal cancer [19], pancreatic cancer [20,21], liver cancer [22], CRC [23,24], etc. and is correlated with poor prognosis [25]. The most recent clinical findings identified that elevated DCLK1+ cells in the blood can be used as a novel non-invasive marker for the diagnosis of incidence, relapse and metastasis for CRC [26], liver cancer [27], pancreatic cancer [28] and Barrett's esophagus and esophageal adenocarcinoma [29].…”