Biology subjects

Bergot, E.

Publications and source records attributed to Bergot, E..

3 recordsLinked to original sources

bioRxiv2025

The pleuroparenchymal fibroelastosis atlas reveals aberrant cell states and their zonation as an alternate roadmap to lung fibrosis

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a progressive interstitial lung disease with higher prevalence in females, histologically characterized by intra-alveolar fibrosis with septal elastosis (AFE). Effective treatments are lacking, highlighting the need to dissect its pathogenesis at single-cell resolution. MethodsWe performed single-nucleus RNA sequencing (snRNAseq) on explanted lungs from a German (n=23) and a French cohort (n=17) of PPFE patients, and controls (n=16). Identified cell populations were localized by immunofluorescence and multiplex RNA in-situ hybridization. Hierarchical phase-contrast computed tomography (HiP-CT) and micro-CT provided 3D spatial context. Reanalyzed snRNAseq data from a Belgian IPF cohort (n=9) served as disease comparator. FindingsWe present the first snRNAseq atlas of PPFEs cellular and structural landscape based on a European multinational cohort. 24 PPFE patients were female (60.0%), while 34 were non-smokers (85.0%). 519,920 nuclear transcriptomes from PPFE and IPF patients, and controls were profiled. We identified PPFE-specific accumulations of MFAP5+PI16+SFRP2+ adventitial and LEPR+ITGA8+SFRP2+DIO2+ elastofibrotic fibroblasts as main drivers of elastotic remodeling in PPFE. Multiple PPFE fibroblast subsets acquire an inflammatory activation state as highlighted by the expression of CXCL12 and CXCL14. This is accompanied by a marked increase in lymphocytes and the formation of tertiary lymphoid structures (TLS) in a disease that was previously considered to be purely elastofibrotic. We identified CTHRC1+ fibrotic fibroblasts and Aberrant Basaloid cells in PPFE as well, forming the "Usual Fibrotic Niche". 3D reconstruction of the pronounced COL15A1+ vascular conglomerate at the border of the elastofibrotic and subpleural fibrosis indicates communication with interlobar veins. Last, we observed a zonation of the PPFE lesion, constructed by the above-mentioned PPFE-associated cell types. InterpretationOur unprecedented cellular and molecular survey uncovers previously unobserved PPFE-specific inflammatory and elastogenic fibroblast populations, as well as the presence of CTHRC1+ fibroblasts and Aberrant Basaloid cells common to other fibrotic ILDs. These findings provide the foundation for including PPFE patients in current antifibrotic trials, as well as development of PPFE-specific therapies. FundingSupported mainly by the Else Kroner-Fresenius Foundation, the German Center for Lung Research and the Fondation du Souffle.

cell biology↗

bioRxiv2023

Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer

The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n=45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumour of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumour specimens.

cancer biology↗

bioRxiv2017

Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells

Tuberculosis (TB) is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobac-terium tuberculosis (MTB), is estimated to have infected up to a third of the worlds population; however, only approximately 10% of infected healthy individuals progress to active TB. Despite evidence for heritability, it is not currently possible to predict who may develop TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from active TB. We measured gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms nearby the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated decent performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.

genomics↗