Résumé
Abstract Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.
Auteurs, date et publication :
Auteurs Stéphanie Lhomond , Tony Avril , Nicolas Dejeans , Konstantinos Voutetakis , Dimitrios Doultsinos , Mari McMahon , Raphaël Pineau , Joanna Obacz , Olga Papadodima , Florence Jouan , Heloise Bourien , Marianthi Logotheti , Gwénaële Jégou , Néstor Pallares-Lupon , Kathleen Schmit , Pierre-Jean Le Reste , Amandine Etcheverry , Jean Mosser , Kim Barroso , Elodie Vauléon
Publication : EMBO Molecular Medicine
Date : 2018
Volume : 10
Issue : 3
Pages : e7929
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Highly differentiated mature spermatozoa carry not only genetic but also epigenetic information that is to be transmitted to the embryo. DNA methylation is one epigenetic actor associated with sperm nucleus compaction, gene silencing, and prepatterning of embryonic gene expression. Therefore, the stability of this mark toward reproductive biotechnologies is a major issue in animal production. The present work explored the impact of hormonal induction of spermiation and sperm cryopreservation in two cyprinids, the goldfish (Carassius auratus) and the zebrafish (Danio rerio), using LUminometric Methylation Assay (LUMA). We showed that while goldfish hormonal treatment did increase sperm production, it did not alter global DNA methylation of spermatozoa. Different sperm samples repeatedly collected from the same males for 2 months also showed the same global DNA methylation level. Similarly, global DNA methylation was not affected after cryopreservation of goldfish spermatozoa with methanol, whereas less efficient cryoprotectants (dimethylsulfoxide and 1,2-propanediol) decreased DNA methylation. In contrast, cryopreservation of zebrafish spermatozoa with methanol induced a slight, but significant, increase in global DNA methylation. In the less compact nuclei, that is, goldfish fin somatic cells, cryopreservation did not change global DNA methylation regardless of the choice of cryoprotectant. To conclude, global DNA methylation is a robust parameter with respect to biotechnologies such as hormonal induction of spermiation and sperm cryopreservation, but it can be altered when the best sperm manipulation conditions are not met.
Auteurs, date et publication :
Auteurs Alexandra Depincé , Anne Gabory , Katarzyna Dziewulska , Pierre-Yves Le Bail , Hélène Jammes , Catherine Labbé
Publication : Molecular Reproduction and Development
Date : 2025
Volume : 87
Issue : 1
Pages : 124-134
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Modern plant breeding and agrosystems artificialization could have altered plants’ ability to filter and recruit beneficial microorganisms in its microbiota. Thus, compared to modern cultivars, we hypothesized that root-endosphere microbiota in modern wheat cultivars are less resistant to colonization by fungi and bacteria and thus more susceptible to also recruit more pathogens. We used an in-field experimental design including six wheat varieties (three ancient vs. three modern) grown in monoculture and in mixture (three replicates each). Endospheric microbiota of wheat roots were analyzed on four individuals sampled randomly in each plot. Composition-based clustering of sequences was then characterized from amplicon mass-sequencing. We show that the bacterial and fungal microbiota composition in wheat roots differed between ancient and modern wheat cultivar categories. However, the responses observed varied with the group considered. Modern cultivars harbored higher richness of bacterial and fungal pathogens than ancient cultivars. Both cultivar types displayed specific indicator species. A synergistic effect was identified in mixtures of modern cultivars with a higher root endospheric mycobiota richness than expected from a null model. The present study shows the effect of plant breeding on the microbiota associated plant roots. The results call for making a diagnosis of the cultivar's endospheric-microbiota composition. These new results also suggest the importance of a holobiont-vision while considering plant selection in crops and call for better integration of symbiosis in the development of next-generation agricultural practices.
Auteurs, date et publication :
Auteurs Solène Mauger , Claire Ricono , Cendrine Mony , Vèronique Chable , Estelle Serpolay , Marine Biget , Philippe Vandenkoornhuyse
Publication : Plant-Environment Interactions
Date : 2025
Volume : 2
Issue : 5
Pages : 235-248
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
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
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
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
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
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