A new subgroup of hepatocellular adenomas with sonic hedgehog pathway activation
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ABSTRACT:
PROVIDER: EGAS00001002091 | EGA |
REPOSITORIES: EGA
Publications
Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation.
Nault Jean-Charles JC Couchy Gabrielle G Balabaud Charles C Morcrette Guillaume G Caruso Stefano S Blanc Jean-Frederic JF Bacq Yannick Y Calderaro Julien J Paradis Valérie V Ramos Jeanne J Scoazec Jean-Yves JY Gnemmi Viviane V Sturm Nathalie N Guettier Catherine C Fabre Monique M Savier Eric E Chiche Laurence L Labrune Philippe P Selves Janick J Wendum Dominique D Pilati Camilla C Laurent Alexis A De Muret Anne A Le Bail Brigitte B Rebouissou Sandra S Imbeaud Sandrine S Bioulac-Sage Paulette P Letouzé Eric E Zucman-Rossi Jessica J
Gastroenterology 20161207 4
<h4>Background & aims</h4>Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.<h4>Methods</h4>We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A ...[more]
Similar Datasets
Project description:Hepatocellular adenomas (HCA) are rare benign tumors that constitute a heterogeneous entity, divided into 5 groups based on molecular features (1) H-HCA with inactivating mutations of Hepatocyte Nuclear Factor 1A (HNF1α), (2) inflammatory HCA (IHCA) with diverse mutations activating the JAK/STAT pathway, (3) b-HCA with activating β-catenin mutation (4) recently identified sh-HCA presenting a Sonic Hedgehog pathway activation and finally, (5) the unclassified HCA (UHCA)). Risk of bleeding of sh-HCA and UHCA is their main clinical feature with malignant transformation. Nowadays, no specific biomarker exists to evaluate this hemorrhage risk. The objective of this study was to combine laser microdissection and mass spectrometry analysis to define Hepatocellular Adenoma proteome in the purpose of identifying specific biomarkers able to predict this bleeding risk.
2018-03-14 | PXD005571 | Pride
Project description:Hepatocellular adenomas (HCA) are rare benign tumors mainly developed in women after 2 years of oral contraceptive use (Rooks et al., 1979). HCA are also related to other risk factors (obesity, vascular diseases, androgen and alcohol intake) or to different genetic diseases (Mac Cune Albright syndrome, glycogen storage diseases type 1a and MODY3 diabetes caused by HNF1A germline mutation) (Calderaro et al., 2013; Nault et al., 2013a). Bleeding and malignant transformation to hepatocellular carcinoma (HCC) can occur as severe complications observed respectively in 30-50% and 5% of the cases. In the past 10 years, we identified 4 major molecular subgroups of HCA defined by (1) mutations inactivating HNF1A (H-HCA, 35% of the HCA) (Bacq et al., 2003; Bluteau et al., 2002; Jeannot et al., 2010), (2) activation of ß-catenin by mutations in exon 3 (bHCA, 15%) (Chen et al., 2002), (3) inflammatory phenotype with STAT3 activation (IHCA, 50%) (Bioulac-Sage et al., 2009; Zucman-Rossi et al., 2006), (4) a tumor subgroup of HCA with Sonic Hedgehog pathway activation due to recurrent focal deletions (shHCA) (Nault et al. ,in preparation) and (5) the remaining unclassified tumors (UHCA, 10%) (Bioulac-Sage et al., 2009). Among bHCA, half displayed both inflammatory and ß-catenin activated phenotypes (bIHCA). Inflammatory adenomas (IHCA) are caused by IL6ST somatic mutation activating gp130 in 60% of the cases (Rebouissou et al., 2009) whereas other IHCA are mutated for STAT3 itself (Pilati et al., 2011) or GNAS (Nault et al., 2012) but in the remaining 30% cases no mutation (NM) were identified yet. This molecular classification is currently accepted in clinical practice using either immunohistochemical markers (Bioulac-Sage et al., 2009; Bioulac-Sage et al., 2007) or in radiology at MRI (Laumonier et al., 2008) and it has dramatically improved the diagnosis and prognostic assessment of HCA. HCC derived from HCA malignant transformation (HCC on HCA, 5%)
2019-10-01 | GSE88839 | GEO
Project description:Sonic Hedgehog subgroup medulloblastomas
| PRJNA384622 | ENA
Project description:The objective of this study was to identify genes regulated by Sonic Hedgehog pathway stimulation in neural progenitors. Paired (parallel culture) triplicates of neuralized embryoid body cultures with and without Shh pathway stimulation (Ag1.3-treatment)
2012-12-15 | E-GEOD-42565 | biostudies-arrayexpress
Project description:Background: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. Results: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-kB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-kB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. Conclusions: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-kB. AMPK-NF-kB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-kB and Shh pathways confers synergy for SHH-MB therapy.
2023-07-01 | GSE218076 | GEO
Project description:The objective of this study was to identify genes regulated by Sonic Hedgehog pathway stimulation in neural progenitors.
2012-12-15 | GSE42565 | GEO
Project description:Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients’ risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.
Related Publication:
Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation
Nault, Jean-CharlesLaurent, Christophe et al.
Gastroenterology , Volume 152 , Issue 4 , 880 - 894.e6
http://dx.doi.org/10.1053/j.gastro.2016.11.042
| EGAD00001003092 | EGA
Project description:Using 10xGenomics single cell RNAseq library creation and Illumina sequencing, we generated single cell RNAseq data for 12 samples of myeloid cells in mouse sonic hedgehog medulloblastomas to characterize their heterogeneity in comparison to control peripheral myeloids cells and homeostatic cerebellar myeloid cells from young mice without significant tumors. We then sequenced myeloid cells in tumors that were treated with two modalities, sonic hedgehog inhibition and radiation, to determine the differential recruitment of myeloid cells. Finally we sequenced samples of myeloid cells from irradiated Ccr2 knockout mice to further determine the change in recruitment of myeloid cells and their heterogeneity when monocyte-derived macrophages are reduced.
2021-02-13 | GSE166691 | GEO
Project description:Sivakumar2011 - Hedgehog Signaling Pathway
This is the current model for the Hedgehog signaling pathway. The best data for mechanism of signaling has been worked out in Drosophila, so this model is based largely on Drosophila data. Hedgehog target genes vary from tissue to tissue, so the identities of individual target genes have not been listed. The main difference between the Drosophila and mammalian Hedgehog signaling pathways is the fact that there are three mammalian homologs of Cubitus interruptus, Gli1 Gli2 and Gli3. Some or all of the mammalian homologs may be proteolytically processed, but the data are controversial. There are two mammalian Ptc genes and three mammalian Hedgehog genes as well. The pathway for Sonic Hedgehog appears to be most similar to the Drosophila hedgehog pathway.
References:
Hedgehog signaling in animal development: paradigms and principles.
Sonic hedgehog in the nervous system: functions, modifications and mechanisms.
Hedgehog signal transduction: recent findings.
Hedgehog signaling: Costal-2 bridges the transduction gap.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
This model is hosted on BioModels Database and identified by: BIOMD0000000395.
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To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000395 | BioModels
Project description:Hepatocellular adenomas (HCA) are rare benign tumours of the liver which have been extensively classified at the clinico-pathological, genetic and proteomic levels. The b-HCA subtype has several types of mutations in the ß-catenin gene (CTNNB1) with very different clinical phenotypes and risks. Recently, we revealed a glutamine synthetase (GS) positive rim in b-HCA exon 3 S45 and b-HCA exon 7/8, indicating protein expression heterogeneity into b-HCA in comparison with the rest of the tumor. A difference in vascularization had been associated with this rim revealed by a diffuse CD34 labeling only at the center of the tumor and not in the rim. In this study, we sought to characterize this tumor heterogeneity in a tumor considered monoclonal. We used laser microdissection to analyze the rim (R) at the molecular level. We cut 1mm² areas of GS+/CD34- rim on serial cuts and we analyzed in parallel, the mutation status of CTNNB1 and the levels of protein expression by mass spectrometry. Comparison of the proteomic profiles of the rim versus the tumor center (T) revealed a sufficiently large protein expression differential to distinguish them by principal component analysis. Forty proteins were significantly differentially expressed between R and T, including a large majority of amino acid and lipid metabolism proteins whose deregulations were comparable to a perivenous expression profile in a normal hepatocyte context. Our results suggest that protein expression in the rim seems not to be dependent on the mutational status of CTNNB1 but rather on the influence of venous drainage. Thanks to laser microdissection coupled with proteomic analysis on fixed tissue, we were able to analyze this tumor heterogeneity and provide elements of biological interpretation.
2023-05-02 | PXD031323 | Pride