Detection of Helium in the Atmosphere of the Exo-Neptune HAT-P-11b

The helium absorption triplet at a wavelength of 10,833 \AA\ has been proposed as a way to probe the escaping atmospheres of exoplanets. Recently this feature was detected for the first time using Hubble Space Telescope (HST) WFC3 observations of the hot Jupiter WASP-107b. We use similar HST/WFC3 observations to detect helium in the atmosphere of the hot Neptune HAT-P-11b at the $4\sigma$ confidence level. We compare our observations to a grid of 1D models of hydrodynamic escape to constrain the thermospheric temperatures and mass loss rate. We find that our data are best fit by models with high mass loss rates of $\dot{M} \approx 10^{9}$ - $10^{11}$ g s$^{-1}$. Although we do not detect the planetary wind directly, our data are consistent with the prediction that HAT-P-11b is experiencing hydrodynamic atmospheric escape. Nevertheless, the mass loss rate is low enough that the planet has only lost up to a few percent of its mass over its history, leaving its bulk composition largely unaffected. This matches the expectation from population statistics, which indicate that close-in planets with radii greater than 2 R$_{\oplus}$ form and retain H/He-dominated atmospheres. We also confirm the independent detection of helium in HAT-P-11b obtained with the CARMENES instrument, making this the first exoplanet with the detection of the same signature of photoevaporation from both ground- and space-based facilities.Comment: 12 pages, 9 figures, accepted for publication in ApJ

“Fibrous nests” in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome

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Effets phénotypiques de deux mécanismes d’activation de la voie Wnt/beta caténine dans le carcinome hépatocellulaire

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Half of them show activation of Wnt/β-catenin pathway, caused by activating CTNNB1 exon 3 mutation of by stimulation of FRZD receptor. Transcriptomic based HCC classifications showed that this two types of activation were associated with distinct tumor subtypes. We tried to better understand the molecular phenotypes and the clinical features associated with these subtypes. In a first part, we linked extracellular Wnt activation with a stem/progenitor phenotype and with fibrous hotspot in HCC. Fibrous hotspot, which were called “fibrous nest”, can be detected by routine anatomic pathology analyses. We also showed that HAPLN1, an extracellular matrix protein induced by Wnt3a in progenitor HepaRG cells, was a new marker of stemness and bad outcome in HCC. Those results shows the associations between extracellular Wnt activation, extracellular matrix remodeling and tumor aggressiveness. In a second part, a transcriptome meta-analysis of 1133 HCCs highlighted 4 robust subclasses. CTNNB1 mutation, predicted by a 5-genes score based method, was associated with one of these subclasses and with good clinical features. We also highlighted a new subclass of CTNNB1 wild type HCCs associated with tumor differentiation, signatures of periportal metabolism and good outcome. This subclass was probably a confounding factor in survival studies comparing HCCs carrying mutant versus those carrying wild-type CTNNB1. Finally, we highlighted strong negative associations between CTNNB1 mutation and inflammation as well as tumor fibrosis in three independent cohorts. Preliminary results of in vitro HepaRG cells mutated for CTNNB1 in T41 and stimulated by LPS suggest an inhibitory effect of β-caténine on NF-κB. In conclusion, our results show that the two types of Wnt activation in HCC are associated with very distinct molecular phenotypes and clinical features.Le carcinome hépatocellulaire (CHC) est une des principales causes de mortalité par cancer dans le monde. Dans environ 50% des tumeurs, on observe les signes d’une activation de la voie Wnt/β-caténine, causée par une mutation de l’exon 3 du gène CTNNB1 ou par stimulation du récepteur FRZD. Des études transcriptomiques du CHCs ont montré que ces deux modes d’activation étaient associés à des sous-types de tumeurs différents. Nous avons cherché à mieux comprendre les caractéristiques cliniques et le phénotype moléculaire de ces deux sous-types de CHCs. Dans un premier temps, nous avons fait le lien entre l'activation Wnt extracellulaire, un phénotype de cellules cancéreuses souches ou progénitrices et la présence de foyers de fibrose discrète intra-tumorale, observable par examen histopathologique, que nous avons appelés "nids fibreux". Nous avons également mis en évidence HAPLN1, une protéine de la matrice extracellulaire dont l’expression est stimulée par Wnt3a dans un modèle de cellules hépatiques progénitrices HepaRG, comme un nouveau marqueur d’agressivité du CHC. Ces résultats montrent une association entre l’activation Wnt extracellulaire et une agressivité tumorale passant par un remodelage matriciel. Dans un second temps, une Méta-analyse de données publiques de transcriptomique a permis de mettre évidence 4 sous-types de CHCs. La mutation CTNNB1, prédite par l’expression de 5 marqueurs par une méthode développée durant la thèse, était associée à un de ces sous-types et à un bon pronostic clinique. Nous avons également isolé un nouveau sous-type de CHC de bon pronostic exprimant un phénotype de tumeur différenciée et des signatures de métabolisme hépatique périportales. Ce sous-type a probablement été un facteur confondant dans les études précédentes mesurant l’association de la mutation CTNNB1 avec un bon pronostic. Enfin, nous avons mis en évidence une forte association négative entre la mutation CTNNB1 et l’inflammation ainsi que la fibrose tumorale dans trois cohortes indépendantes. Cet effet pourrait être provoqué par une inhibition de NF-κB par la β-caténine mutée, comme suggérée par des résultats préliminaires issue d’un modèle in vitro d’HepaRG mutés T41 stimulés par LPS. Nos résultats suggèrent donc que les deux modes d’activation de la voie Wnt/β-caténine sont associés à des mécanismes moléculaires, des profils d’expression, des phénotypes et des pronostics cliniques très différents

Molecular phenotypes and clinical features associated with two types of Wnt/beta catenin activation in hepatocellular carcinoma

Le carcinome hépatocellulaire (CHC) est une des principales causes de mortalité par cancer dans le monde. Dans environ 50% des tumeurs, on observe les signes d’une activation de la voie Wnt/β-caténine, causée par une mutation de l’exon 3 du gène CTNNB1 ou par stimulation du récepteur FRZD. Des études transcriptomiques du CHCs ont montré que ces deux modes d’activation étaient associés à des sous-types de tumeurs différents. Nous avons cherché à mieux comprendre les caractéristiques cliniques et le phénotype moléculaire de ces deux sous-types de CHCs. Dans un premier temps, nous avons fait le lien entre l'activation Wnt extracellulaire, un phénotype de cellules cancéreuses souches ou progénitrices et la présence de foyers de fibrose discrète intra-tumorale, observable par examen histopathologique, que nous avons appelés "nids fibreux". Nous avons également mis en évidence HAPLN1, une protéine de la matrice extracellulaire dont l’expression est stimulée par Wnt3a dans un modèle de cellules hépatiques progénitrices HepaRG, comme un nouveau marqueur d’agressivité du CHC. Ces résultats montrent une association entre l’activation Wnt extracellulaire et une agressivité tumorale passant par un remodelage matriciel. Dans un second temps, une Méta-analyse de données publiques de transcriptomique a permis de mettre évidence 4 sous-types de CHCs. La mutation CTNNB1, prédite par l’expression de 5 marqueurs par une méthode développée durant la thèse, était associée à un de ces sous-types et à un bon pronostic clinique. Nous avons également isolé un nouveau sous-type de CHC de bon pronostic exprimant un phénotype de tumeur différenciée et des signatures de métabolisme hépatique périportales. Ce sous-type a probablement été un facteur confondant dans les études précédentes mesurant l’association de la mutation CTNNB1 avec un bon pronostic. Enfin, nous avons mis en évidence une forte association négative entre la mutation CTNNB1 et l’inflammation ainsi que la fibrose tumorale dans trois cohortes indépendantes. Cet effet pourrait être provoqué par une inhibition de NF-κB par la β-caténine mutée, comme suggérée par des résultats préliminaires issue d’un modèle in vitro d’HepaRG mutés T41 stimulés par LPS. Nos résultats suggèrent donc que les deux modes d’activation de la voie Wnt/β-caténine sont associés à des mécanismes moléculaires, des profils d’expression, des phénotypes et des pronostics cliniques très différents.Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Half of them show activation of Wnt/β-catenin pathway, caused by activating CTNNB1 exon 3 mutation of by stimulation of FRZD receptor. Transcriptomic based HCC classifications showed that this two types of activation were associated with distinct tumor subtypes. We tried to better understand the molecular phenotypes and the clinical features associated with these subtypes. In a first part, we linked extracellular Wnt activation with a stem/progenitor phenotype and with fibrous hotspot in HCC. Fibrous hotspot, which were called “fibrous nest”, can be detected by routine anatomic pathology analyses. We also showed that HAPLN1, an extracellular matrix protein induced by Wnt3a in progenitor HepaRG cells, was a new marker of stemness and bad outcome in HCC. Those results shows the associations between extracellular Wnt activation, extracellular matrix remodeling and tumor aggressiveness. In a second part, a transcriptome meta-analysis of 1133 HCCs highlighted 4 robust subclasses. CTNNB1 mutation, predicted by a 5-genes score based method, was associated with one of these subclasses and with good clinical features. We also highlighted a new subclass of CTNNB1 wild type HCCs associated with tumor differentiation, signatures of periportal metabolism and good outcome. This subclass was probably a confounding factor in survival studies comparing HCCs carrying mutant versus those carrying wild-type CTNNB1. Finally, we highlighted strong negative associations between CTNNB1 mutation and inflammation as well as tumor fibrosis in three independent cohorts. Preliminary results of in vitro HepaRG cells mutated for CTNNB1 in T41 and stimulated by LPS suggest an inhibitory effect of β-caténine on NF-κB. In conclusion, our results show that the two types of Wnt activation in HCC are associated with very distinct molecular phenotypes and clinical features

Tumor microenvironment‐derived serum markers as a new frontier of diagnostic and prognostic assessment in biliary tract cancers

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REPLY: Intratumor fibrotic HCC, a subtype matching the Hoshida S1 subclass?

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The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals

International audienceGlutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957 357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation

An aggressive subgroup of CTNNB1-mutated hepatocellular carcinomas with STEM-cell phenotype and immune tolerance

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MOLECULAR CHARACTERIZATION OF THE EXTRACELLULAR MATRIX OF HEPATOCELLULAR CARCINOMA EXHIBITING INTRATUMOR FIBROSIS IDENTIFIES A CANCER-SPECIFIC SIGNATURE

International audienceMeeting Abstract 448

Hepatocellular carcinomas, exhibiting intratumor fibrosis, express cancer-specific extracellular matrix remodeling and WNT/TGFB signatures, associated with poor outcome

International audienceBACKGROUND AIMS: Hepatocellular carcinoma (HCC), the third cause of cancer-related death, arises in the context of liver fibrosis (LF). Although HCC is generally poorly fibrogenic, some tumors harbor focal intratumor extracellular matrix (ECM) deposits, called fibrous nests. To date, the molecular composition and the clinical relevance of these ECM deposits has not been fully defined. APPROACH RESULTS: We performed quantitative matrisome analysis by tandem mass tags mass spectrometry (TMT-MS) in 20 human HCCs, with high- or low-grade intratumor fibrosis, and matched non-tumor (NT) tissues, as well as in 12 livers from mice treated with vehicle, CCl4 or diethylnitrosamine (DEN). We found 94 ECM proteins differentially abundant between high- and low-grade fibrous nests, including interstitial and basement membrane components, such as several collagens, glycoproteins, proteoglycans, enzymes involved in ECM stabilization and degradation, and growth factors. Pathway analysis revealed a metabolic switch in high-grade fibrosis, with enhanced glycolysis and decreased oxidative phosphorylation. Integrating our quantitative proteomics data with the transcriptomes from HCCs and NT livers (n = 2,285 samples), we identified a subgroup of fibrous nest HCCs, characterized by cancer-specific ECM remodeling, expression of the WNT/TGFB (S1) subclass signature, and poor patient outcome. Fibrous nest HCCs, abundantly expressed an 11 fibrous nest proteins’ signature, associated with poor patient outcome, by multivariate Cox analysis, and validated by multiplex immunohistochemistry. CONCLUSION: Matrisome analysis highlighted cancer-specific ECM deposits, typical of the WNT/TGFB HCC subclass, associated with poor patient outcome. Hence, histological reporting of intratumor fibrosis in HCC is of clinical relevance