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DCLK1 Marks a Morphologically Distinct Subpopulation of Cells with Stem Cell Properties in Pre-invasive Pancreatic Cancer

ABSTRACT: 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. Whole transcriptome anlaysis of AcTub Hi vs AcTub Low cells. Cells were labeled with an acetylated alpha tubulin antibody that recognized epitopes on the cell surface (AAT+). AcTub Hi vs Low cells were FACS sorted from the human pancreatic cancer cell lines CFPAC and AsPC1 CFPAC and AsPC1 cells were labeling with AcTub (acetylated alpha tubulin antibody) and then FACS sorted based on high or low levels of AcTub, and microarray analyses were run on biological replicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Bailey Jennifer

PROVIDER: S-ECPF-GEOD-52406 | biostudies-other |

REPOSITORIES: biostudies-other

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DCLK1 Marks a Morphologically Distinct Subpopulation of Cells with Stem Cell Properties in Pre-invasive Pancreatic Cancer

Project description: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. Whole transcriptome anlaysis of AcTub Hi vs AcTub Low cells. Cells were labeled with an acetylated alpha tubulin antibody that recognized epitopes on the cell surface (AAT+). AcTub Hi vs Low cells were FACS sorted from the human pancreatic cancer cell lines CFPAC and AsPC1 CFPAC and AsPC1 cells were labeling with AcTub (acetylated alpha tubulin antibody) and then FACS sorted based on high or low levels of AcTub, and microarray analyses were run on biological replicates.

2013-11-16 | E-GEOD-52406 | biostudies-arrayexpress

DCLK1 Marks a Morphologically Distinct Subpopulation of Cells with Stem Cell Properties in Pre-invasive Pancreatic Cancer

2013-11-16 | GSE52406 | GEO

DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer.

Project description:Background & aimsAs 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, it 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 preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties.MethodsPancreatic tissue samples were collected from the KC(Pdx1), KPC(Pdx1), and KC(iMist1) mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses.ResultsThe microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological 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. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression.ConclusionsHuman 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.

| S-EPMC3910427 | biostudies-literature

RHAMM marks proliferative subpopulation of human colorectal cancer stem cells.

Project description:The cancer stem cell (CSC) theory features typically rare self-renewing subpopulations that reconstitute the heterogeneous tumor. Identification of molecules that characterize the features of CSCs is a key imperative for further understanding tumor heterogeneity and for the development of novel therapeutic strategies. However, the use of conventional markers of CSCs is still insufficient for the isolation of bona fide CSCs. We investigated organoids that are miniature forms of tumor tissues by reconstructing cellular diversity to identify specific markers to characterize CSCs in heterogeneous tumors. Here, we report that the receptor for hyaluronan-mediated motility (RHAMM) expresses in a subpopulation of CD44+ conventional human colorectal CSC fraction. Single-cell transcriptomics of organoids highlighted RHAMM-positive proliferative cells that revealed distinct characteristics among the various cell types. Prospectively isolated RHAMM+CD44+ cells from the human colorectal cancer tissues showed highly proliferative characteristics with a self-renewal ability in comparison with the other cancer cells. Furthermore, inhibition of RHAMM strongly suppressed organoid formation in vitro and inhibited tumor growth in vivo. Our findings suggest that RHAMM is a potential therapeutic target because it is a specific marker of the proliferative subpopulation within the conventional CSC fraction.

| S-EPMC10323086 | biostudies-literature

Mex3a Marks a Slowly Dividing Subpopulation of Lgr5+ Intestinal Stem Cells.

Project description:Highly proliferative Lgr5+ stem cells maintain the intestinal epithelium and are thought to be largely homogeneous. Although quiescent intestinal stem cell (ISC) populations have been described, the identity and features of such a population remain controversial. Here we report unanticipated heterogeneity within the Lgr5+ ISC pool. We found that expression of the RNA-binding protein Mex3a labels a slowly cycling subpopulation of Lgr5+ ISCs that contribute to all intestinal lineages with distinct kinetics. Single-cell transcriptome profiling revealed that Lgr5+ cells adopt two discrete states, one of which is defined by a Mex3a expression program and relatively low levels of proliferation genes. During homeostasis, Mex3a+ cells continually shift into the rapidly dividing, self-renewing ISC pool. Chemotherapy and radiation preferentially target rapidly dividing Lgr5+ cells but spare the Mex3a-high/Lgr5+ population, helping to promote regeneration of the intestinal epithelium following toxic insults. Thus, Mex3a defines a reserve-like ISC population within the Lgr5+ compartment.

| S-EPMC5774992 | biostudies-literature

CD98 marks a subpopulation of head and neck squamous cell carcinoma cells with stem cell properties

Project description:The application of compounds specifically targeting the cancer stem cells (CSCs), in addition to routinely used therapeutics, would likely improve the clinical outcome of head and neck squamous cell carcinoma (HNSCC). The previously described monoclonal antibody K984 (now found to recognize CD98) was used to identify, select and isolate a specific tumor subpopulation. These cells were molecularly characterized and subjected to serial transplantation experiments to determine the CSC properties. We show that CD98high cells, in contrast to CD98low cells, are able to generate tumors in immunodeficient mice and that the CD98high subpopulation expresses high levels of cell cycle control and DNA repair genes, while the CD98low fraction shows expression patterns that represent the more differentiated cells forming the bulk of the tumor. Transcriptional profiling of CD98high cells (n=4 fractions) of VU-SCC-OE xenograft tumors compared to CD98low cells (n=3 fractions) from the corresponding tumors.

2015-01-24 | E-GEOD-35477 | biostudies-arrayexpress

The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells.

Project description:ObjectiveCancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes.DesignMicro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs.ResultsWe found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-β1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer.ConclusionsOur findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.

| S-EPMC4680182 | biostudies-literature

CD98 marks a subpopulation of head and neck squamous cell carcinoma cells with stem cell properties

2015-01-24 | GSE35477 | GEO

A slow-cycling subpopulation of melanoma cells with highly invasive properties.

Project description:Melanoma is a heterogeneous tumor with different subpopulations showing different proliferation rates. Slow-cycling cells were previously identified in melanoma, but not fully biologically characterized. Using the label-retention method, we identified a subpopulation of slow-cycling cells, defined as label-retaining cells (LRC), with strong invasive properties. We demonstrate through live imaging that LRC are leaving the primary tumor mass at a very early stage and disseminate to peripheral organs. Through global proteome analyses, we identified the secreted protein SerpinE2/protease nexin-1 as causative for the highly invasive potential of LRC in melanomas.

| S-EPMC5799768 | biostudies-literature

CRX Expression in Pluripotent Stem Cell-Derived Photoreceptors Marks a Transplantable Subpopulation of Early Cones.

Project description:Death of photoreceptors is a common cause of age-related and inherited retinal dystrophies, and thus their replenishment from renewable stem cell sources is a highly desirable therapeutic goal. Human pluripotent stem cells provide a useful cell source in view of their limitless self-renewal capacity and potential to not only differentiate into cells of the retina but also self-organize into tissue with structure akin to the human retina as part of three-dimensional retinal organoids. Photoreceptor precursors have been isolated from differentiating human pluripotent stem cells through application of cell surface markers or fluorescent reporter approaches and shown to have a similar transcriptome to fetal photoreceptors. In this study, we investigated the transcriptional profile of CRX-expressing photoreceptor precursors derived from human pluripotent stem cells and their engraftment capacity in an animal model of retinitis pigmentosa (Pde6brd1), which is characterized by rapid photoreceptor degeneration. Single cell RNA-Seq analysis revealed the presence of a dominant cell cluster comprising 72% of the cells, which displayed the hallmarks of early cone photoreceptor expression. When transplanted subretinally into the Pde6brd1 mice, the CRX+ cells settled next to the inner nuclear layer and made connections with the inner neurons of the host retina, and approximately one-third of them expressed the pan cone marker, Arrestin 3, indicating further maturation upon integration into the host retina. Together, our data provide valuable molecular insights into the transcriptional profile of human pluripotent stem cells-derived CRX+ photoreceptor precursors and indicate their usefulness as a source of transplantable cone photoreceptors. Stem Cells 2019;37:609-622.

| S-EPMC6519156 | biostudies-literature

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