The role of Lgr5 intestinal cancer stem cells in tumour initiation, progression and metastasis
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PROVIDER: PRJNA359185 | ENA |
REPOSITORIES: ENA
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Project description:Gastric cancer is amongst the most prevalent and deadliest cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a stomach-specific Claudin18-IRES-CreERT2 mouse line to model advanced human gastric cancer and investigated the role of tumour resident Lgr5+ stem-like cells in gastric cancer. Mouse lines incorporating Cldn18-driven conditional dysregulation of the Wnt, RTK and Trp53 pathways modelled metastatic Chromosomal Instable-type gastric cancer. In parallel, we supplemented these cancer models with orthotopic transplantation of cancer organoids to derive detailed mechanistic insight into the roles of Lgr5+ cancer stem cell in gastric cancer. Here we show, we recapitulated advanced human gastric cancer in terms of disease phenotype, aberrant gene expression profile, molecular markers, and sites of distant metastases. Importantly, we established that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden, and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically-relevant mechanistic insights into cancer progression and as pre-clinical models for evaluating novel therapeutics.
2021-11-26 | GSE184613 | GEO
Project description:Almost all colorectal cancers (CRC) present with mutations in the Apc gene, leading to unrestrained Wnt activation and the initiation of tumour development. We previously reported the competitive benefit of Apc-mutant intestinal stem cells (ISCs) within the crypt, however, the mechanism by which they outcompete their wild type (WT) neighbours remained elusive. Here, we studied the effect of Apc-mutants using an in vitro culture system of WT (Lgr5-CreErt2) and Apc-/- (Lgr5-CreErt2;Apcfl/fl) organoids . The expression patterns of WT and Apc-/- organoids revealed significant upregulation in specific secreted Wnt antagonists Notum, Wif1 and Dkk2. Furthermore, we studied the effect of the secreted antagonist by treating WT organoids with either WT or Apc-/- conditioned medium (CM) for 48 hours and observed a significant decrease in stem cell markers and an increase in goblet cell markers. We report that Apc-mutants act as bona fide supercompetitors by secreting Wnt antagonists that result in active differentiation of WT ISCs.
2021-03-25 | GSE144325 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-03-29 | GSE92966 | GEO
Project description:Apc-mutants act as supercompetitors in intestinal tumour initiation
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Project description:KRAS allelic imbalance drives a MAPK dependent tumour initiation programme inefficient at rewiring the tumour microenvironment to provoke metastasis
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Project description:We previously identified Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal tumors. In this study, we have identified IL17RB as a cell surface marker distinctively expressed by Dclk1+ tuft-like tumor cells in mouse intestinal tumors. Using this tuft cell marker, we compared and analyzed the transcriptome of Lgr5-tuft marker-, Lgr5+tuft marker-, Lgr5-tuft marker+, and Lgr5+tuft marker+ tumor cells. These analyses revealed that tuft-like tumor cells in the intestinal tumors comprise two distinct subsets: highly differentiated tuft-like tumor cells (Lgr5-tuft marker+ cells) and tuft-like tumor cells with TCS potential (Lgr5+tuft marker+ cells).
2021-02-19 | GSE118853 | GEO
Project description:We analyzed gene expression of 3 lines LGR5-GFP, 2 lines KRT20-GFP knock-in colorectal tumor organdies. The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+ colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5+ tumour cells. Selective ablation of LGR5+ CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+ CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+ CSCs and contributing to tumour regrowth after LGR5+ CSC ablation. We also show that combined chemotherapy potentiates LGR5+ CSCs targeting. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.
2017-03-30 | GSE83513 | GEO
Project description:Development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic, but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating Ptgs2, Tnf, and Ccl/Cxcl 86 cytokines, known to promote brain vascular remodeling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting of exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.
2021-09-08 | PXD015210 | Pride
Project description:Lgr5+ crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a novel Lgr5-2A-DTR (Diphtheria Toxin Receptor) model which ablates Lgr5+ cells with near-complete efficiency and retains endogenous levels of Lgr5 expression, we show that persistent depletion of Lgr5+ ISCs in fact compromises SI epithelial integrity and reduces epithelial turnover in vivo. In vitro, Lgr5-2A-DTR SI organoids are unable to establish or survive when Lgr5+ ISCs are continuously eliminated when DT is in the media. However, transient exposure to DT at the start of culture allows organoids to form, and the rate of outgrowth reduces with increasing length of DT presence. Our results indicate that intestinal homeostasis requires a constant pool of Lgr5+ ISCs, which is supplied by rapidly reprogrammed non-Lgr5+ crypt populations when pre-existing Lgr5+ ISCs are ablated.
2020-12-31 | GSE148727 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE40171: RNA sequencing of circulating tumour cells implicates WNT signaling in pancreatic cancer metastasis (mouse data) GSE40174: RNA sequencing of circulating tumour cells implicates WNT signaling in pancreatic cancer metastasis (human data) Refer to individual Series
2012-08-17 | E-GEOD-40176 | biostudies-arrayexpress