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GSE79495
Mus musculus
15 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Canonical Wnt signalling regulates the self-renewal of most if not all stem cell systems. In the blood system, the role of Wnt signalling has been subject of much debate, with positive and negative roles of Wnt signalling proposed for hematopoietic stem cells (HSC). As we have shown previously, this controversy can be largely explained by the effects of different dosages of Wnt signalling. What remained unclear however, was why high Wnt signals would lead to loss of reconstituting capacity. To better understand this phenomenon, we have taken advantage of a series of hypomorphic mutant Apc alleles resulting in a broad range of Wnt dosages in HSCs, purified those HSCs and performed whole genome gene expression analyses. Gene expression profiling and functional studies show that HSCs with APC mutations lead to high Wnt levels , enhanced differentiation and diminished proliferation, but have no effect on apoptosis, collectively leading to loss of stemness. Thus, we provide mechanistic insight into the role of APC mutations and Wnt signalling in HSC biology. As Wnt signals are explored in various in vivo and ex vivo expansion protocols for HSCs, our findings also have clinical ramifications.
Publication Title
High Levels of Canonical Wnt Signaling Lead to Loss of Stemness and Increased Differentiation in Hematopoietic Stem Cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Cancer stemness in Wnt-driven mammary tumorigenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The Wnt/beta-catenin signalling pathway plays a central role in mammary stem cell homeostasis and in breast cancer. We employed the CD29hiCD24+ cell surface antigens to identify a subpopulation of mammary CSCs from Apc1572T/+, a mouse model for metaplastic breast adenocarcinoma, a subtype of triple-negative breast cancer in man. The MaCSCs are capable of recapitulating tumorigenesis when transplanted at low multiplicities in vivo, and of forming self-renewing organoids in vitro. Expression profiling of the different subpopulations sorted from normal and neoplastic mammary tissues revealed that the normal stem cell compartment is more similar to tumor cells than to their own differentiated progenies. Accordingly, Wnt signaling was found to be activated in the subpopulation encompassing normal mammary stem cells, though to a lesser degree than in the tumor cells. By comparing normal with cancer mouse mammary compartments, we were able to derive a MaCSC-specific signature composed of human orthologous genes able to predict poor survival, relapse and distant metastasis in human breast cancer. Finally, upon intravenous injection, only MaCSCs among the different tumor cell subpopulations are able to form metastatic lesions in a broad spectrum of anatomical sites. Overall, our data indicate that constitutive Wnt signaling activation interferes with mammary stem cell homeostasis leading to metaplasia and basal-like adenocarcinomas.
Publication Title
Cancer stemness in Wnt-driven mammary tumorigenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Constitutive activation of the Wnt pathway leads to adenoma formation, an obligatory step towards intestinal cancer. In view of the established role of Wnt in regulating stemness, we attempted the isolation of cancer stem cells (CSCs) from Apc- and Apc/KRAS-mutant intestinal tumours. Whereas CSCs are present in malignant Apc/KRASmutant carcinomas, they appear to be very rare (<10-6) in the benign Apcmutant adenomas. In contrast, the Lin-CD24hiCD29+ subpopulation of adenocarcinoma cells appear to be enriched in CSCs with increased levels of active -catenin. Expression profiling analysis of the CSC-enriched subpopulation confirmed their enhanced Wnt activity and revealed additional differential expression of other signalling pathways, growth factor binding proteins, and extracellular matrix components. As expected, genes characteristic of the Paneth cell lineage (e.g. defensins) are co-expressed together with stem cell genes (e.g. Lgr5) within the CSC-enriched subpopulation. This is of interest as it may indicate a cancer stem cell niche role for tumor-derived Paneth-like cells, similar to their role in supporting Lgr5+ stem cells in the normal intestinal crypt. Overall, our results indicate that oncogenic KRAS activation in Apc-driven tumours results in the expansion of the CSCs compartment by increasing b-catenin intracellular stabilization.
Publication Title
Cancer stemness in Apc- vs. Apc/KRAS-driven intestinal tumorigenesis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 5 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
The majority of sporadic colorectal cancer cases are initiated by mutations in the APC tumor suppressor gene leading to constitutive activation of the Wnt/b-catenin signaling pathway and adenoma formation. Several pre-clinical models carrying germline mutations in the endogenous mouse Apc tumor supressor gene have been generated and their phenotype characterized. The predisposition of these mouse models to multiple intestinal adenomas closely resembles the FAP phenotype at the molecular, cellular and phenotypic level and may prove valuable to elucidate the molecular and cellular mechanisms underlying colorectal tumorigenesis. The goal of this study is to establish an expression signature characteristic of intestinal tumors characterized by the inactivation of Apc.
Publication Title
Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The cancer-risk associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long non-coding RNA CCAT2 in the highly amplified 8q24.21 region has been implicated in cancer predisposition, though causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by downregulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel disease-specific RNA mutation (named DNA-to-RNA allelic imbalance, DRAI) at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.
Publication Title
Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA <i>CCAT2</i> induce myeloid malignancies via unique SNP-specific RNA mutations.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 86 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Metastatic melanoma is a deadly disease while non-metastatic melanoma and other cutaneous tumor types are usually cured with surgical removal of the primary tumors. This study evaluated gene expresion to determine if gene expression differences existed which would allow one to identify the metastatic tumors based on the expression of specific genes.
Publication Title
The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels.
Publication Title
Deletion of PARP-2 induces hepatic cholesterol accumulation and decrease in HDL levels.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
IlluminaHiSeq2500
Description
Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. Here, we demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes derived from lung tropic models can redirect metastasis to the lung. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastasis. Whereas exosomal integrins a6ß4 and a6ß1 were associated with lung metastasis, exosomal integrins avß5 and avß3 were linked with liver and brain metastases, respectively. Targeting a6ß4 and avß5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Importantly, we demonstrate that exosome uptake activates a cell-specific subset of S100 family genes, known to support cell migration and niche formation. Finally, our clinical data indicate that integrin-expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. Overall design: Education of human von Kupffer cells in vitro with human pancreatic cancer exosomes
Publication Title
Tumour exosome integrins determine organotropic metastasis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 38 Downloadable Samples
- Illumina HiSeq 2500
Description
Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 (Usp15L749R) that protected mice against both experimental cerebral malaria (ECM) induced by Plasmodium berghei and experimental autoimmune encephalomyelitis (EAE). Combining immunophenotyping and RNA sequencing in brain (ECM) and spinal cord (EAE) revealed that Usp15L749R-associated resistance to neuroinflammation was linked to dampened type I interferon responses in situ. In hematopoietic cells and in resident brain cells, USP15 was coexpressed with, and functionally acted together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses and to promote pathogenesis during neuroinflammation. The USP15-TRIM25 dyad might be a potential target for intervention in acute or chronic states of neuroinflammation. Overall design: Sequencing of RNA extracted from target tissue in two experimental neuroinflammation models in wild-type (B6), USP15(L749R) and Trim25 KO mutant mice: (1) brains at day 3 and 5 following Plasmodium berghei ANKA (PbA) infection for the cerebral malaria model (ECM); and (2) spinal cords at day 7 following induction of experimental autoimmune encephalomyelitis (EAE) for B6 and Usp15 mutant mice only.
Publication Title
USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples