Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
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PROVIDER: PRJNA432079 | ENA |
REPOSITORIES: ENA
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Project description:In order to dissect pathways enchained in skeletal stem/progenitors by Fibrous Dysplasia mutations, we engineered human skeletal stem/progenitors with the mutation and performed transcriptomic analysis. FD mutation profoundly alters the properties of skeletal stem/progenitors by pushing hBMSCs towards formation of disorganized bone with a concomitant lack of fat development. In addition, the mutation created an altered in trans environment that pushed the overall system towards neovascularization, inflammation and osteoclastogenesis. We used microarrays to detail the global programme of gene expressionc of human skeletal progenitors containing the Gsα activating mutation R201C
2018-07-01 | GSE109818 | GEO
Project description:Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets.
| S-EPMC6991960 | biostudies-literature
Project description:Background and Aims: Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer, although underlying mechanisms are incompletely understood. We sought to identify a potential gene expression signature in non-dysplastic distal mucosa that as a “genetic field effect” could be a marker for remote neoplastic lesions. Results: 468 genes were significantly up-regulated and 541 genes were significantly down-regulated >2-fold in UC patients with neoplasia compared to UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly up-regulated from controls to quiescent non-dysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increases in tissue expression of S100A9 and REG1 in UC-associated cancer and in non-dysplastic tissue from UC patients harboring remote neoplasia, compared to UC patients without dysplasia and normal controls. Conclusions: Gene expression changes occur as a field effect in UC patients without active inflammation who harbor a remote dysplastic lesion. Further characterization of these genes and proteins might elucidate pathways of carcinogenesis in IBD and lead to the development of more accurate, less invasive markers of dysplasia in those at increased risk.
2012-04-20 | GSE37283 | GEO
Project description:Background and Aims: Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer, although underlying mechanisms are incompletely understood. We sought to identify a potential gene expression signature in non-dysplastic distal mucosa that as a “genetic field effect” could be a marker for remote neoplastic lesions. Results: 468 genes were significantly up-regulated and 541 genes were significantly down-regulated >2-fold in UC patients with neoplasia compared to UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly up-regulated from controls to quiescent non-dysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increases in tissue expression of S100A9 and REG1 in UC-associated cancer and in non-dysplastic tissue from UC patients harboring remote neoplasia, compared to UC patients without dysplasia and normal controls. Conclusions: Gene expression changes occur as a field effect in UC patients without active inflammation who harbor a remote dysplastic lesion. Further characterization of these genes and proteins might elucidate pathways of carcinogenesis in IBD and lead to the development of more accurate, less invasive markers of dysplasia in those at increased risk. Microarray assay were conducted on 20 RNA samples isolated from colon mucosa of 20 patients. Of these patients, 5 were normal controls, 4 had quiescent UC, and 11 had UC with neoplasia. Patients were included if they had a previous clinical diagnosis of UC confirmed by an expert GI pathologist, a disease duration > 7 years, and an extent of disease >20 cm proximal to the anal verge.
2012-04-19 | E-GEOD-37283 | biostudies-arrayexpress
Project description:To investigate transcriptomic profiles of of two dysplastic stem cell (DSC) subpopulations, CD44v6neg/CD133+/CD166+ (DP-DSC) and CD44v6+/CD133+/CD166+ (TP-DSC), in dysplastic organoids (Meta4 organoids) established from active-Kras induced mouse stomachs
2022-09-28 | GSE202191 | GEO
Project description:Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major primary liver cancers in adults. It has been shown the phenotypic overlap between HCC and CC, comprising continuous liver cancer spectrum. As a proof of concept, a recent study has demonstrated a genomic subtype of HCC expressing CC-like gene expression trait, i.e. CC-like HCC, which has revealed common genomic trait of stem cell-like property and aggressive clinical outcome. However, the histopathological characteristics of these intermediate phenotype was not fully evaluated yet. Here, we found that a variant HCC with fibrous stromal component, i.e. scirrhous HCC, has CC-like genomic features. By performing gene expression profiling and immunohistochemical evaluation, we compared the morphological and molecular features of scirrhous HCC with CC and classical HCC. We found that the scirrhous HCC express both CC-like and stem cell-like expression traits. In addition, we observed the expression of core epithelial-mesenchymal transition (EMT)-related genes, which may contribute to the aggressive behavior of scirrhous HCC. Over-expression of transforming growth factor β (TGF-β) signaling was also found, implying its regulatory role in the pathobiology of scirrhous HCC. Conclusion: We suggest that the fibrous stromal component in HCC may contribute to the acquisition of CC-like gene expression trait in HCC. The expression of stem cell-like trait and TGF-β/EMT molecules may play pivotal roles in the aggressive phenotype of scirrhous HCC Gene expression profiles of HCC, CC and HCC with fibrous stroma were compared.
2012-08-31 | E-GEOD-31370 | biostudies-arrayexpress
Project description:A single-cell transcriptional analysis was performed on lung epithelial cells isolated from influenza PR8 infected mice at 14 days post injury. The goal is to investigate the potential signaling pathway that regulates dysplastic KRT5 cells expansion. The left lung lobe from influenza infected mice were dissociated to single cells and subjected to fluorescence activated cell sorting (FACS) to select all Epcam+ cells. We found that the regulation of actin cytoskeleton, focal adhesion, Hippo signaling pathway are highly activated in dysplastic KRT5+ cells, suggesting that these signaling pathway may play a role in the expansion of dysplastic KRT5 cells in influenza infected lungs.
2024-07-31 | GSE234082 | GEO
Project description:Correct chromosome segregation during cell division depends on proper connections between spindle microtubules and kinetochores. During prometaphase, kinetochores are temporarily covered with a dense protein meshwork known as the fibrous corona. Formed by oligomerization of ROD/ZW10/ZWILCH-SPINDLY (RZZ-S) complexes, the fibrous corona promotes spindle assembly, chromosome orientation and spindle checkpoint signaling. The molecular requirements for formation of the fibrous corona are not fully understood. Here we show that the fibrous corona depends on the mitotic kinesin CENP-E, and that poorly expanded fibrous coronas after CENP-E depletion are functionally compromised. This previously unrecognized role for CENP-E does not require its motor activity but instead is driven by its C-terminal microtubule-binding region and farnesyl modification thereof. The ‘birth’ of a farnesylation motif in CENP-E orthologs during Obazoa evolution closely aligns with presence of the full RZZ-S module, and we show that in cells CENP-E interacts with RZZ-S complexes in a farnesyl-dependent manner. CENP-E is recruited to kinetochores following RZZ-S, and - while not required for RZZ-S oligomerization per se - promotes subsequent fibrous corona expansion. Our results show that proper spindle assembly has a non-motor contribution from the kinesin CENP-E through stabilization of the fibrous corona meshwork during its formation.
2023-10-09 | PXD040338 | Pride
Project description:Background: The risk of developing Barrett’s esophagus (BE) and/or esophageal adenocarcinoma (EAC) is associated with specific demographic and behavioral factors, including gender, obesity/elevated body-mass index (BMI), and tobacco use. Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC. It is currently unknown whether obesity or tobacco smoking influence the risk of developing BE/EAC via the induction of alterations in DNA methylation. To investigate this possibility, we assessed the genome-wide methylation status of 81 esophageal tissues, including BE, dysplastic BE, and EAC epithelia using HumanMethylation450 BeadChips (Illumina). Results: We found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to nonsmokers. Differences in DNA methylation between these groups were seen in a variety of functional genomic regions, and both within and outside of CpG islands. Several cancer-related pathways were found to have differentially methylated genes between these comparison groups. Conclusions: Our findings suggest obesity and tobacco smoking may influence DNA methylation in the esophagus and raise the possibility that these risk factors affect the development of BE, dysplastic BE, and EAC through influencing the epigenetic status of specific loci that have a biologically plausible role in cancer formation.
2016-10-25 | GSE89181 | GEO
Project description:To investigate whether the CD44v6neg/CD133+/CD166+ dysplastic stem cells are responsible for gastric adenocarcinoma development and cancer cell heterogeneity in the stomach, we used single cell RNA-seq (scRNA-seq) to examine gene expression profiles of heterogenous cancer cells in two types of gastric adenocarcinoma, cystic type and tubular type, developed from the dysplastic stem cell injection under the skin of immunodeficient nude mice.
2022-09-28 | GSE202192 | GEO