Résumé
Epigenetic mechanisms are believed to play key roles in the establishment of cell-specific transcription programs. Accordingly, the modified bases 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been observed in DNA of genomic regulatory regions such as enhancers, and oxidation of 5mC into 5hmC by Ten-eleven translocation (TET) proteins correlates with enhancer activation. However, the functional relationship between cytosine modifications and the chromatin architecture of enhancers remains elusive. To gain insights into their function, 5mC and 5hmC levels were perturbed by inhibiting DNA methyltransferases and TETs during differentiation of mouse embryonal carcinoma cells into neural progenitors, and chromatin characteristics of enhancers bound by the pioneer transcription factors FOXA1, MEIS1, and PBX1 were interrogated. In a large fraction of the tested enhancers, inhibition of DNA methylation was associated with a significant increase in monomethylation of H3K4, a characteristic mark of enhancer priming. In addition, at some specific enhancers, 5mC oxidation by TETs facilitated chromatin opening, a process that may stabilize MEIS1 binding to these genomic regions.
Auteurs, date et publication :
Auteurs Elise A. Mahé , Thierry Madigou , Aurélien A. Sérandour , Maud Bizot , Stéphane Avner , Frédéric Chalmel , Gaëlle Palierne , Raphaël Métivier , Gilles Salbert
Publication : Genome Research
Date : 2017
Volume : 27
Issue : 6
Pages : 947-958
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. 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 highlights novel drug vulnerabilities that can be exploited to develop long-lasting antimelanoma therapies.
Auteurs, date et publication :
Auteurs Arthur Gautron
Publication : EMBO Molecular Medicine
Date : 2021
Volume : 13
Issue : 5
Pages : e13466
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
In the initial, online publication, the authors' given names were captured as family names and vice versa. The names are correctly shown here. The original article has been corrected.
Auteurs, date et publication :
Auteurs Paloma Compes , Emeline Tabouret , Amandine Etcheverry , Carole Colin , Romain Appay , Nicolas Cordier , Jean Mosser , Olivier Chinot , Hervé Delingette , Nadine Girard , Henry Dufour , Philippe Metellus , Dominique Figarella-Branger
Publication : Journal of Neuro-Oncology
Date : 2019
Volume : 142
Issue : 3
Pages : 521-521
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is highly metastatic. Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment.
OBJECTIVE: To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC.
PATIENTS AND METHODS: For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib. The expression of c-MET was correlated with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular criteria (VHL status) by univariate and multivariate analyses and to clinical outcome using Kaplan-Meier curves compared by log-rank test.
RESULTS: Of ccRCC, 31.1% had low c-MET expression (absent to weak intensity by IHC) versus 68.9% with high expression (moderate to strong intensity). High expression of c-MET was associated with a gain in FISH analysis (p=0.0284) without amplification. No mutations were detected in NGS. Moreover, high c-MET expression was associated with lymph node metastases (p=0.004), sarcomatoid component (p=0.029), VEGFA (p=0.037), and PD-L1 (p=0.001) overexpression, the only factor that remained independently associated (p<0.001) after logistic regression. No difference was observed in clinical outcomes.
CONCLUSION: This study is the first to analyse c-MET status in metastatic ccRCC. The high expression of c-MET in the majority of ccRCC and its independent association with PD-L1 expression, may suggest a potential benefit from combining c-MET inhibitors and targeted immunotherapy.
Auteurs, date et publication :
Auteurs Solène-Florence Kammerer-Jacquet , Sarah Medane , Karim Bensalah , Jean-Christophe Bernhard , Mokrane Yacoub , Frantz Dupuis , Alain Ravaud , Grégory Verhoest , Romain Mathieu , Benoit Peyronnet , Angélique Brunot , Brigitte Laguerre , Alexandra Lespagnol , Jean Mosser , Frédéric Dugay , Marc-Antoine Belaud-Rotureau , Nathalie Rioux-Leclercq
Publication : Targeted Oncology
Date : 2017
Volume : 12
Issue : 4
Pages : 487-494
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
The rhizosphere microbiome has been shown to contribute to nutrient acquisition, protection against biotic and abiotic stresses and, ultimately, to changes in the development and physiology of plants. Here, using a controlled natural selection approach, we followed the microbial dynamics in the soil of Arabidopsis thaliana plants infected with the foliar pathogen Pseudomonas syringae DC3000 (Pst).
Auteurs, date et publication :
Auteurs Tetiana Kalachova , Barbora Jindřichová , Lenka Burketová , Cécile Monard , Manuel Blouin , Samuel Jacquiod , Eric Ruelland , Ruben Puga-Freitas
Publication : Plant and Soil
Date : 2022
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Targeted sequencing of 16S rDNA amplicons is routinely used for microbial community profiling but this method suffers several limitations such as bias affinity of universal primers and short read size. Gene capture by hybridization represents a promising alternative. Here we used a metagenomic extract from the pea aphid Acyrthosiphon pisum to compare the performances of two widely used PCR primer pairs with DNA capture, based on solution hybrid selection. All methods produced an exhaustive description of the 8 bacterial taxa known to be present in this sample. In addition, the methods yielded similar quantitative results, with the number of reads strongly correlating with quantitative PCR controls. Both methods can thus be considered as qualitatively and quantitatively robust on such a sample with low microbial complexity.
Auteurs, date et publication :
Auteurs Marie Cariou , Céline Ribière , Stéphanie Morlière , Jean-Pierre Gauthier , Jean-Christophe Simon , Pierre Peyret , Sylvain Charlat
Publication : BMC Research Notes
Date : 2018
Volume : 11
Issue : 1
Pages : 1-5
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Abstract
Introduction
Patients with stage IV non–small-cell lung cancer (NSCLC) and BRAF V600 mutations may benefit from targeted therapies. Chemotherapy outcomes are little known in this population.
Methods
The French Cooperative Thoracic Intergroup (IFCT) Biomarkers France study was a national prospective cohort study aiming to describe the molecular characteristics and clinical outcome of all consecutive NSCLC patients (N = 17,664) screened for molecular alterations. We used this data set to set up a case–control analysis. Cases had stage IV BRAF-mutated (BRAF-MT) NSCLC, whereas controls had NSCLC that was wild-type for EGFR, KRAS, HER2, BRAF, PIK3CA and ALK. Each case was matched for sex, age at diagnosis and smoking status to two controls randomly selected.
Results
Overall, 83 cases with BRAF mutant disease (66.3% V600E) were matched to 166 controls. Five cases received tyrosine kinase inhibition in the first-line and 16 in the second-line. All others were treated with standard chemotherapy. There was no significant difference in first-line and second-line progression-free survival (PFS) between the groups, as well as in the disease control rate, BRAF mutation was not found to be prognostic of overall survival. We found no significant difference in outcome between the treatment types used in first-line or second-line in patients with BRAF-MT disease compared with controls nor between BRAF V600E or non-V600E compared with controls.
Conclusions
BRAF mutation is not a strong prognostic factor in NSCLC. Although taxan-based therapy shows poorest PFS in first-line, no chemotherapy regimen was associated with prognosis.
Auteurs, date et publication :
Auteurs Sébastien Couraud , Fabrice Barlesi , Clara Fontaine-Deraluelle , Didier Debieuvre , Jean-Philippe Merlio , Lionel Moreau , Michèle Beau-Faller , Rémi Veillon , Jean Mosser , Faraj Al Freijat , Pierre-Paul Bringuier , Hervé Léna , L'Houcine Ouafik , Virginie Westeel , Alain Morel , Clarisse Audigier-Valette , Pascale Missy , Alexandra Langlais , Franck Morin , Pierre-Jean Souquet
Publication : European Journal of Cancer
Date : 2019
Volume : 116
Pages : 86-97
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
The holobiont concept defines a given organism and its associated symbionts as a potential level of selection over evolutionary time. In clonal plants, recent experiments demonstrated vertical transmission of part of the microbiota from one ramet (i.e., potentially autonomous individual) to another within the clonal network (i.e., connections by modified stems present in ∼35% of all plants). Because of this heritability, and potentially reciprocal exchange of microbes between generations of ramets, we propose to extend the existing holobiont framework to the concept of meta-holobiont. A meta-holobiont is a network of holobionts that can exchange biomolecules and microbiota across generations, thus impacting the fitness of both biological scales: holobionts and meta-holobionts. Specifically, meta-holobiont dynamics can result in sharing, specialization, and division of labor across plant clonal generations. This paper, which coins the meta-holobiont concept, is expected to stimulate discussion and to be applied beyond the context of networked clonal plants (e.g., to social insects).
Auteurs, date et publication :
Auteurs Nathan Vannier , Cendrine Mony , Anne-Kristel Bittebiere , Kevin R. Theis , Eugene Rosenberg , Philippe Vandenkoornhuyse
Publication : mSystems
Date : 2019
Volume : 4
Issue : 2
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Background: EGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database.
Patients and methods: Of 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients.
Results: EGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61-0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02-2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49-0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96-2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53-0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.
Conclusion: EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.
Auteurs, date et publication :
Auteurs C. Leduc , J. P. Merlio , B. Besse , H. Blons , D. Debieuvre , P. P. Bringuier , I. Monnet , I. Rouquette , S. Fraboulet-Moreau , A. Lemoine , D. Pouessel , J. Mosser , F. Vaylet , A. Langlais , P. Missy , F. Morin , D. Moro-Sibilot , J. Cadranel , F. Barlesi , M. Beau-Faller
Publication : Annals of Oncology: Official Journal of the European Society for Medical Oncology
Date : 2017
Volume : 28
Issue : 11
Pages : 2715-2724
Catégorie(s)
#CNRS #EcoGenO #Université de RennesAuteurs, date et publication :
Auteurs Nicolas Guibert , Fabrice Barlesi , Renaud Descourt , Hervé Lena , Benjamin Besse , Michèle Beau-Faller , Jean Mosser , Eric Pichon , Jean-Philippe Merlio , l'Houcine Ouafik , François Guichard , Bénédicte Mastroianni , Lionel Moreau , Annie Wdowik , Jean-Christophe Sabourin , Antoinette Lemoine , Pascale Missy , Alexandra Langlais , Denis Moro-Sibilot , Julien Mazières
Publication : Journal of Thoracic Oncology
Date : 2017
Volume : 12
Issue : 6
Pages : 963