DCLK1 Marks a Morphologically Distinct Subpopulation of Cells With Stem Cell Properties in Preinvasive Pancreatic Cancer

Abstract

Background & Aims As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether pre-invasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. Methods Pancreatic tissue samples were collected from the KCPdx1, KPCPdx1, and KCiMist1 mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human PDAC cells were similarly analyzed and also used in cDNA microarray analyses. Results The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphologic and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacologic inhibition of γ–secretase activity reduced the abundance of these cells in murine PanIN, in a manner that correlated with inhibition of PanIN progression. Conclusions Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis, and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.

Functional implication of Dclk1 and Dclk1-expressing cells in cancer

“…Dclk1C cells isolated from pancreatic cancer cells lines were found to be highly tumorigenic. 13 Finally, our group recently reported on the ability of pancreatic Dclk1C cells to serve as a potent source of preinvasive pancreatic cancer initiating cells in the setting of Kras mutation and pancreatic injury. Overall, growing evidence from in vivo and in vitro studies suggests that Dclk1C cells can function as cancer stem and cancer initiating cells in colorectal and pancreatic cancer.…”

“…Through a series of elegant studies, the authors were able to show that these Dclk1C cells possess features of cancer stem (initiating) cells. 13 Moreover, we recently demonstrated, that Dclk1 marks pancreatic progenitor cells that play a pivotal role in pancreatic regeneration and are a powerful source of cancer initiating cells in the context of pancreatic injury 14 (Fig. 2).…”

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

“…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). [77][78][79][80] It is also worth mentioning that the other protease gene that is notably upregulated upon acquisition of metformin resistance, in addition to KLK11 and CTSF, is the gene coding for the serine hydrolase enzyme monoacylglycerol lipase (MAGL) ( Table 2).…”

Stem Cells in Pancreatic Cancer

“…As this subpopulation is identifiable at very early stages during adenocarcinoma development, it provides new targets for early diagnostic and drug testing [21].…”