Biology subjects

Gentien, D.

Publications and source records attributed to Gentien, D..

6 recordsLinked to original sources

bioRxiv2023

Plakins are involved in the maintenance of epithelial polarity

As epithelia are the interface between the organism and the external environment, they are often subject to damage and must be frequently renewed. However, maintaining epithelial integrity during this renewal is challenging, and loss of cell polarity is a potent inducer of tumorigenesis. In this study, we used transcriptomic data from breast cancer cells at different stages of tumor development to identify molecular changes associated with the early stages of tumor transformation. We correlated these protein expression profiles with either cell polarity defects or cell progression along the epithelial-to-mesenchymal transition (EMT). We identified plakins, namely epiplakin (EPPK1), desmoplakin (DSP) and periplakin (PPL), that were downregulated in cells that had lost their epithelial polarity and also downregulated in cells that had progressed through EMT. We further tested them experimentally by knocking down their expression in a non-tumorigenic epithelial breast cell line (MCF10A). We demonstrated their causal role in the loss of polarity, as revealed by the misorientation of the nuclear centrosome vector. We also found that vimentin, a marker of EMT, was overexpressed in plakin knocked-down cells, suggesting that plakins may have both a structural and a regulatory role in maintaining the epithelial state.

cell biology↗

bioRxiv2022

Optical Genome Mapping for detecting Homologous Recombination Deficiency (HRD) in human breast cancers

Homologous recombination deficiency (HRD) leads to genomic instability that marks HRD tumor genome with a specific genomic scar. Present in many cancers, HRD is important to be detected as it is associated with a hyper-sensitivity to some classes of drugs, in particular the PARP inhibitors. Here, we investigated the use of structural variants (SVs) detected by the Optical Genome Mapping (OGM) technology as biomarkers to identify HRD tumors. We analyzed SVs data obtained by OGM from 37 samples of triple-negative breast cancer or high grade ovarian cancer with the known HRD status. We found that HRD cases were enriched with duplications and reciprocal translocations, while nonHRD cases were enriched with inversions. The number of translocations, defined as inter-chromosomal or intra-chromosomal rearrangements of more 5Mb were similar in HRD and nonHRD cases. We defined isolated translocations as the subset of translocations having no other translocation within 2 megabase zone around both junctions, and demonstrated that the number of isolated translocations perfectly discriminated HRD and nonHRD cases in the training series. Validation series consisting from 26 cases showed 20% false positive and zero false negative error rate, which proved isolated translocations to be 100% sensitive and 80% specific SV marker of HRD. Our results demonstrate that the OGM technology is an affordable way of getting an insight of the structural variants present in solid tumors, even with low tumoral cellularity. It represents a promising technology for HRD diagnosis, where a single marker already gives 80% correct recognition.

cancer biology↗

bioRxiv2022

Multi-omics comparison of malignant and normal uveal melanocytes reveals novel molecular features of uveal melanoma.

Uveal Melanoma (UM) is a rare cancer resulting from transformation of melanocytes residing in the uveal tract. Integrative analysis has identified four molecular and clinical subsets in UM. To improve our molecular understanding of UM we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis by Hi-C. Our gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. We also identified a recurrent deletion in the BAP1 promoter resulting in loss of expression and associated with high risk of metastases in UM patients. Hi-C revealed chromatin topology changes associated with up-regulation of PRAME, an independent prognostic biomarker in UM and potential therapeutic target. Our findings illustrate how multi-omics approaches can improve the understanding of tumorigenesis and reveals two novel mechanisms of gene expression dysregulation in UM.

genomics↗

bioRxiv2022

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Muscle-invasive bladder cancer (BLCA) is an aggressive disease. Consensus BLCA transcriptomic subtypes have been proposed, with two major Luminal and Basal subgroups, presenting distinct molecular and clinical characteristics. However, how these distinct subtypes are regulated remains unclear. We hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of BLCA subtypes. Through integrated RNA-sequencing and epigenomic profiling of histone marks in primary tumours, cancer cell lines, and normal human urothelia, we established the first integrated epigenetic map of BLCA and demonstrated the link between subtype and epigenetic control. We identified the repertoire of activated super-enhancers and highlighted Basal, Luminal and Normal-associated SEs. We revealed the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal subgroups including FOXA1 and ZBED2 respectively. FOXA1 CRISPR-Cas9 mutation triggered a shift from Luminal to Basal phenotype, confirming its role in Luminal identity regulation and induced ZBED2 overexpression. In parallel, we showed that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in cancer cells through STAT2 inhibition. Our study furthers the understanding of epigenetic regulation of muscle-invasive BLCA and identifies a co-regulated network of super-enhancers and associated transcription factors providing potential targets for the treatment of this aggressive disease.

cancer biology↗

bioRxiv2021

PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. Its depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. The enzymatic activity of PRMT1 is also required to stimulate the canonical Wnt pathway. Recently developed type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients, as well as the EGFR inhibitor, erlotinib. Therefore, targeting PRMT1 in combination with drugs used in the clinic may improve current treatments for TNBC patients. SignificanceThis study highlights the requirement of PRMT1 for breast cancer cell survival and demonstrates the potential of targeting type I PRMTs in combination with chemotherapies in triple-negative breast cancer.

cancer biology↗

bioRxiv2017

Molecular insights into the pathways underlying naked mole-rat eusociality

BackgroundEusociality is the highest level of social organization and naked mole-rats (NMR)s are amongst the few mammals showing this unique social behavior; nevertheless, little is known about the molecular mechanisms underlying the eusociality of NMRs.\n\nResultsGene expression profiling of NMR brain and gonads (ovary and testis), from animals belonging to different reproductive castes, revealed robust gene expression differences between reproductive and non-reproductive members of NMR colonies. In the brain, dopaminergic pathways appear to be potential players in NMR eusocial behaviour. Breeding animals (queens and breeding males) showed increased expression of genes involved in dopamine metabolism. Using immunohistochemistry, we notably found these differences to be in dopaminergic hypothalamic areas, which provide inhibitory control over the secretion of prolactin, amongst other regions. Furthermore, plasma prolactin concentrations were elevated in many non-breeders (of both sexes), often reaching levels exceeding that of pregnant or lactating queens, suggesting a role for hyperprolactinaemia in socially-induced reproductive suppression. We also found that the ovaries of non-breeding females are arrested at pre-pubertal stage. They contained fewer supporting stromal cells compared to queens, and had very low expression of the aromatase gene Cyp19A1 (a key enzyme in estrogen synthesis) compared to non-breeding females. In the testes, genes involved in post meiosis spermatogenesis and sperm maturation (Prm1, Prm2, Odf3 and Akap4) were highly expressed in breeding males compared to non-breeders, explaining the low sperm number and impaired sperm motility characteristic of non-breeding males.\n\nConclusionsOur study suggests that extreme reproductive skew, one of the defining features of eusociality, is associated with changes in expression of key components of dopamine pathways, which could lead to hypogonadism and a lifetime of socially-induced sterility for most NMRs.

neuroscience↗