Résumé
Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor that is characterized in most cases by inactivation of the tumor suppressor gene VHL. The VHL/HIF/VEGF pathway thus plays a major role in angiogenesis and is currently targeted by anti-angiogenic therapy. The emergence of resistance is leading to the use of targeted immunotherapy against immune checkpoint PD1/PDL1 that restores antitumor immune response. The correlation between VHL status and PD-L1 expression has been little investigated. In this study, we retrospectively reviewed 98 consecutive cases of ccRCC and correlated PD-L1 expression by immunohistochemistry (IHC) with clinical data (up to 10-year follow-up), pathological criteria, VEGF, PAR-3, CAIX and PD-1 expressions by IHC and complete VHL status (deletion, mutation and promoter hypermethylation). PD-L1 expression was observed in 69 ccRCC (70.4%) and the corresponding patients had a worse prognosis, with a median specific survival of 52 months (p = 0.03). PD-L1 expression was significantly associated with poor prognostic factors such as a higher ISUP nucleolar grade (p = 0.01), metastases at diagnosis (p = 0.01), a sarcomatoid component (p = 0.04), overexpression of VEGF (p = 0.006), and cytoplasmic PAR-3 expression (p = 0.01). PD-L1 expression was also associated with dense PD-1 expression (p = 0.007) and with ccRCC with 0 or 1 alteration(s) (non-inactivated VHL tumors; p = 0.007) that remained significant after multivariate analysis (p = 0.004 and p = 0.024, respectively). Interestingly, all wild-type VHL tumors (no VHL gene alteration, 11.2%) expressed PD-L1. In this study, we found PD-L1 expression to be associated with noninactivated VHL tumors and in particular wild-type VHL ccRCC, which may benefit from therapies inhibiting PD-L1/PD-1.
Auteurs, date et publication :
Auteurs Solène-Florence Kammerer-Jacquet , Laurence Crouzet , Angélique Brunot , Julien Dagher , Adélaïde Pladys , Julien Edeline , Brigitte Laguerre , Benoit Peyronnet , Romain Mathieu , Grégory Verhoest , Jean-Jacques Patard , Alexandra Lespagnol , Jean Mosser , Marc Denis , Yosra Messai , Sophie Gad-Lapiteau , Salem Chouaib , Marc-Antoine Belaud-Rotureau , Karim Bensalah , Nathalie Rioux-Leclercq
Publication : International Journal of Cancer
Date : 2017
Volume : 140
Issue : 1
Pages : 142-148
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Abstract
Ferriphaselus amnicola GF-20 is the first Fe-oxidizing bacterium isolated from the continental subsurface. It was isolated from groundwater circulating at 20 m depth in the fractured-rock catchment observatory of Guidel-Ploemeur (France). Strain GF-20 is a neutrophilic, iron- and thiosulfate-oxidizer and grows autotrophically. The strain shows a preference for low oxygen concentrations, which suggests an adaptation to the limiting oxygen conditions of the subsurface. It produces extracellular stalks and dreads when grown with Fe(II) but does not secrete any structure when grown with thiosulfate. Phylogenetic analyses and genome comparisons revealed that strain GF-20 is affiliated with the species Ferriphaselus amnicola and is strikingly similar to Ferriphaselus amnicola strain OYT1 which was isolated from a groundwater seep in Japan. Based on the phenotypic and phylogenetic characteristics, we propose that GF-20 represents a new strain within the species Ferriphaselus amnicola.
Auteurs, date et publication :
Auteurs M Garry , J Farasin , L Drevillon , A Quaiser , C Bouchez , T Le Borgne , S Coffinet , A Dufresne
Publication : FEMS Microbiology Ecology
Date : 2024
Pages : fiae047
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Background Rice is the second most produced crop worldwide, but it is highly susceptible to drought-induced yield loss. Micro-organisms can potentially alleviate the negative effects of drought but how they are associated with their host is unclear. The aim of the present study was to unravel the genetic factors involved in this process, and whether it plays a role in rice drought tolerance.
Results To achieve this, we characterized the composition of the root-mycobiota in 296 rice accessions (Oryza sativaL. subsp. indica), grown in the field under control and drought conditions. A Genome Wide Association Study (GWAS) was used to identify marker-trait associations between rice Single Nucleotide Polymorphism (SNP) markers and root mycobiota. This resulted in the identification of ten significant (LOD > 4) SNPs associated with six root associated fungi and four significant SNPs associated with fungi-mediated drought tolerance. The analysis of the genes underlying the loci of the significant markertrait associations identified a priori candidates including genes known to be involved in pathogen defense, abiotic stress responses and cell-wall remodeling processes.
Conclusion Our study shows that the rice genetics affects the recruitment of fungi, some of which affect yield under drought, and provides candidate gene targets for breeding to improve rice-fungal interactions and drought tolerance.
Auteurs, date et publication :
Auteurs Beatriz Andreo-Jimenez , Dennis E. te Beest , Willem Kruijer , Nathan Vannier , Niteen N. Kadam , Giovanni Melandri , S. V. Krishna Jagadish , Gerard Linden , Carolien Ruyter-Spira , Philippe Vandenkoornhuyse , Harro J. Bouwmeester
Date : 2023
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Adipose tissue is an organ with metabolic, endocrine and immune functions. In this tissue, the expressions of genes associated with several metabolic pathways, including lipid metabolism, have been shown to be affected by genetic selection for feed efficiency, an important trait to consider in livestock. We hypothesized that the stimulation of immune system caused by poor hygiene conditions of housing impacts the molecular and cellular features of adipose tissue and that the impact may differ between pigs that diverge in feed efficiency. At the age of 12 weeks, Large White pigs from two genetic lines divergent for residual feed intake (RFI) were housed in two contrasting hygiene conditions (good vs poor). After six weeks of exposure, pigs were slaughtered (n = 36). Samples of blood, subcutaneous (SCAT) and perirenal (PRAT) adipose tissues were collected for cell response and gene expression investigations. The decrease in the relative weight of PRAT was associated with a decline in mRNA levels of FASN, ME, LCN2 and TLR4 (P < 0.05) in pigs housed in poor conditions compared with pigs housed in good conditions for both RFI lines. In SCAT, the expressions of only two key genes (PPARG and TLR4) were significantly affected by the hygiene of housing conditions. Besides, the mRNA levels of both LCN2 and GPX3 were influenced by the RFI line (P 0.05). We also investigated the expressions of genes involved in the immune response and lipid metabolism in whole blood cells cultured in the absence and presence of LPS. The hygiene conditions had no effect but, the relative expression of the GPX3 gene was higher (P < 0.001) in high RFI than in low RFI pigs while the expressions of IL-10 (P = 0.027), TGFβ1 (P = 0.023) and ADIPOR2 (P = 0.05) genes were lower in high RFI than in low RFI pigs. Overall, the current study indicates that the hygiene of housing had similar effects on both RFI lines on the expression of genes in adipose tissues and on the features of SCAT adipose cells and whole blood cells in response to TNF-α and LPS. It further demonstrates that the number of genes with expression impacted by housing conditions was higher in PRAT than in SCAT. It suggests a depot-specific response of adipose tissue to the current challenge.
Auteurs, date et publication :
Auteurs Audrey Quéméner , Marie-Hélène Perruchot , Frédéric Dessauge , Annie Vincent , Elodie Merlot , Nathalie Le Floch , Isabelle Louveau
Publication : PeerJ
Date : 2022
Volume : 10
Pages : e14405
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
INTRODUCTION: The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib.
MATERIALS AND METHODS: In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect.
RESULTS: HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival.
CONCLUSION: HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation.
Auteurs, date et publication :
Auteurs Solène-Florence Kammerer-Jacquet , Angelique Brunot , Karim Bensalah , Boris Campillo-Gimenez , Mathilde Lefort , Sahar Bayat , Alain Ravaud , Frantz Dupuis , Mokrane Yacoub , Gregory Verhoest , Benoit Peyronnet , Romain Mathieu , Alexandra Lespagnol , Jean Mosser , Julien Edeline , Brigitte Laguerre , Jean-Christophe Bernhard , Nathalie Rioux-Leclercq
Publication : Urologic Oncology
Date : 2017
Volume : 35
Issue : 10
Pages : 603.e7-603.e14
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
ABSTRACT
Most genetic alterations that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non-genetic mechanisms that drive these processes. Here, we performed in vivo gain-of-function CRISPR screens and identified SMAD3, BIRC3 and SLC9A5 as key actors of BRAFi-resistance and these genes promote the tumor growth capability of persister cells. We show that their expression levels increase during acquisition of BRAFi-resistance, and remain high in persister cells and during relapse. The upregulation of the SMAD3 transcriptional activity (SMAD3-signature) promotes a mesenchymal-like phenotype and BRAFi-resistance by acting as an upstream transcriptional regulator of potent BRAFi-resistance genes such as EGFR and AXL. This SMAD3-signature predicts resistance to both current melanoma therapies in different cohorts. Critically, chemical inhibition of SMAD3 may constitute amenable target for melanoma since it efficiently abrogates persister cells survival. Interestingly, decrease of SMAD3 activity can also be reached by inhibiting the aryl hydrocarbon receptor (AhR), another druggable transcription factor governing SMAD3 expression level. Our work expands our understanding of the biology of persister cells and highlight novel drug vulnerabilities that can be exploited to develop long-lasting antimelanoma therapies.
Auteurs, date et publication :
Auteurs Arthur Gautron , Laura Bachelot , Anaïs M. Quéméner , Sébastien Corre , Marc Aubry , Florian Rambow , Anaïs Paris , Nina Tardif , Héloïse M. Leclair , Cédric Coulouarn , Jean-Christophe Marine , Marie-Dominique Galibert , David Gilot
Publication : bioRxiv
Date : 2020
Pages : 2020.07.08.193102
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Dietary methionine affects protein metabolism, lean gain and growth performance and acts in the control of oxidative stress. When supplied in large excess relative to growth requirements in diets for pigs, positive effects on pork quality traits have been recently reported. This study aimed to decipher the molecular and biochemical mechanisms affected by a dietary methionine supply above growth requirements in the loin muscle of finishing pigs. During the last 14 days before slaughter, crossbred female pigs (n = 15 pigs/diet) were fed a diet supplemented with hydroxy-methionine (Met5; 1.1% of methionine) or not (CONT, 0.22% of methionine). Blood was sampled at slaughter to assess key metabolites. At the same time, free amino acid concentrations and expression or activity levels of genes involved in protein or energy metabolism were measured in the longissimus lumborum muscle (LM). The Met5 pigs exhibited a greater activity of creatine kinase in plasma when compared with CONT pigs. The concentrations of free methionine, alpha-aminobutyric acid, anserine, 3-methyl-histidine, lysine, and proline were greater in the LM of Met5 pigs than in CONT pigs. Expression levels of genes involved in protein synthesis, protein breakdown or autophagy were only scarcely affected by the diet. Among ubiquitin ligases, MURF1, a gene known to target creatine kinase and muscle contractile proteins, and OTUD1 coding for a deubiquitinase protease, were up-regulated in the LM of Met5 pigs. A lower activity of citrate synthase, a reduced expression level of ME1 acting in lipogenesis but a higher expression of PPARD regulating energy metabolism, were also observed in the LM of Met5 pigs compared with CONT pigs. Principal component analysis revealed that expression levels of many studied genes involved in protein and energy metabolism were correlated with meat quality traits across dietary treatments, suggesting that subtle modifications in expression of those genes had cumulative effects on the regulation of processes leading to the muscle transformation into meat. In conclusion, dietary methionine supplementation beyond nutritional requirements in pigs during the last days before slaughter modified the free amino acid profile in muscle and its redox capacities, and slightly affected molecular pathways related to protein breakdown and energy metabolism. These modifications were associated with benefits on pork quality traits.
Auteurs, date et publication :
Auteurs Florence Gondret , Nathalie Floc'h , Dolores I. Batonon-Alavo , Marie-Hélène Perruchot , Yves Mercier , Bénédicte Lebret
Publication : Animal
Date : 2021
Volume : 15
Pages : 100268
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Polar regions are characterized by rocky terrains with sparse vegetation and oligotrophic soils, i.e. “fellfields”. In such ecosystems, microbial communities should be essential for soil-plant functioning but their diversity is poorly explored. The sub-Antarctic Kerguelen Islands fellfields are characterized by an endemic long-lived cushion plant, Lyallia kerguelensis which rhizosphere may be a shelter for microbes in this harsh environment. Cushions are affected by necrosis and we expect the rhizomicrobiome composition to be related to plant necrosis. We analysed bacterial and fungal communities in bulk- and rhizospheric soils from L. kerguelensis in five different fellfields across the Kerguelen Islands using 16S rRNA and ITS1 metabarcoding. We found that soil microbial communities were composed of both restricted and cosmopolitan taxa. While all sites were dominated by the same bacterial taxa (Chloroflexi, Actinobacteria, α-Proteobacteria and Acidobacteria), the relative abundance of the main fungal phyla (Ascomycota, Basidiomycota, Mortierellomycota and Rozellomycota) highly differed between sites. L. kerguelensis rhizomicrobiome was at least as diverse as the bulk soil, making the rhizosphere a possible reservoir of microbial diversity. It was composed of the same main bacterial phyla than detected in the bulk soil while the composition of the rhizosphere fungal communities was specific to each plant. No common microorganisms were identified regarding cushion necrosis extent across plants and sites, but several microbial putative functions were shared, suggesting a possible shift in soil functioning with cushion necrosis increase. Our study brings new information on the diversity and composition of the microbial communities of fellfield soils in a sub-Antarctic Island and the rhizomicrobiome of a characteristic endemic cushion plant.
Auteurs, date et publication :
Auteurs Lorène Julia Marchand , Françoise Hennion , Michèle Tarayre , Marie-Claire Martin , Benoit Renaud Martins , Cécile Monard
Publication : Frontiers in Soil Science
Date : 2025
Volume : 2
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
The role of Epigenetics in Epithelial Mesenchymal Transition (EMT) has recently emerged. Two epigenetic enzymes with paradoxical roles have previously been associated to EMT, EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 (PRC2) Subunit), a lysine methyltranserase able to add the H3K27me3 mark, and the histone demethylase KDM6B (Lysine Demethylase 6B), which can remove the H3K27me3 mark. Nevertheless, it still remains unclear how these enzymes, with apparent opposite activities, could both promote EMT. In this study, we evaluated the function of these two enzymes using an EMT-inducible model, the lung cancer A549 cell line. ChIP-seq coupled with transcriptomic analysis showed that EZH2 and KDM6B were able to target and modulate the expression of different genes during EMT. Based on this analysis, we described INHBB, WTN5B, and ADAMTS6 as new EMT markers regulated by epigenetic modifications and directly implicated in EMT induction.
Auteurs, date et publication :
Auteurs Camille Lachat , Diane Bruyère , Amandine Etcheverry , Marc Aubry , Jean Mosser , Walid Warda , Michaël Herfs , Elodie Hendrick , Christophe Ferrand , Christophe Borg , Régis Delage-Mourroux , Jean-Paul Feugeas , Michaël Guittaut , Eric Hervouet , Paul Peixoto
Publication : Cancers
Date : 2020
Volume : 12
Issue : 12
Pages : 3649
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
The hologenome concept considers the entity formed by a host and its microbiota, the holobiont, as new level of hierarchical organization subject to neutral and selective forces. We used grafted plants to evaluate the hologenome concept. If deterministic forces shape plant holobionts, then grafted plants will exhibit a particular signature in the root microbiota community, the holobiont composition. Reciprocally, if the microbiota of these chimeric plants is randomly assembled, the hologenome concept would be of limited importance for plants. We analyzed the root-endosphere microbiota of two independent model plant systems including ungrafted and reciprocal-grafting treatments. Consistent with the idea that co-evolution shapes at least in part host-microbiota combinations, grafted and ungrafted hosts harbor markedly different microbiota compositions. The results indicate a non-random assembly of bacterial communities inhabiting the root endosphere of chimeric plants with a stronger effect of the rootstock than scion on the recruitment of microorganisms. Because chimeric plants did not have a random microbiota, the null hypothesis that holobionts assemble randomly and hologenome concept is an intellectual construction only can be rejected. The study supports the relevance of hologenome as biological level of organization and opens new avenues for a better fundamental understanding of plants as holobionts.
Auteurs, date et publication :
Auteurs Marine Biget , Tingting Wang , Cendrine Mony , Qicheng Xu , Lucie Lecoq , Veronique Chable , Kevin R. Theis , Ning Ling , Philippe Vandenkoornhuyse
Date : 2022