Biology subjects

Rebours, V.

Publications and source records attributed to Rebours, V..

4 recordsLinked to original sources

bioRxiv2025

Autophagy driven by VPS34 enables differentiated cell plasticity and cancer initiation

Differentiated cell plasticity and autophagy are fundamental mechanisms of tissue repair. To investigate their integration to maintain tissue homeostasis, we developed a unique model in which VPS34, the highly conserved class III PI3K that promotes autophagic flux, was inactivated in pancreatic exocrine cells, recognised study models. Using scRNAseq, we found that VPS34-null acinar cells evolved towards a transcriptional identity present at low levels in mouse and human pancreas. Functionally, it unexpectedly prevented transdifferentiation, chronic pancreatitis and precancer initiation triggered by stressors. Mechanistically, the newly differentiated cell state was less susceptible to cancer promotion by oncogenic KRAS, through reduced class I PI3K and increased lysosomal degradation of pro-inflammatory REG3A. This result opens the so far unreachable possibility of strategies for protection from environmentally induced cancer initiation.

pathology↗

bioRxiv2023

Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: a bottom-up approach

BackgroundPancreatic ductal adenocarcinoma (PDAC) tumor inter-patient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intra-patient heterogeneity has been reported but has not yet been extensively studied due to the lack of standardized, reproducible and easily accessible high throughput methods. Material and MethodsWe built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multi-step process. The successive stages of i) an in-silico selection from a review literature and a bulk transcriptome analysis of 309 PDACs, ii) a tumor-specific selection from 30 patient-derived xenografts followed by iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n=95, whole-slide, n=148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based-analysis in tumor and pre-neoplastic epithelial areas and a k-means clustering to identify relevant marker combinations. ResultsSequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: 1 classical, 1 intermediate (KRT17+) and 2 basal-like (MUC16+ vs S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival, even in classical predominant PDACs (HR=2.36, p=0.01). Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis may follow a progressive evolution from classical toward a basal through an early intermediate phenotype. ConclusionOur IHC panel redefined and easily assessed the high degree of intra- and inter-tumoral heterogeneity of PDAC.

cancer biology↗

bioRxiv2022

PACpAInt: a deep learning approach to identify molecular subtypes of pancreatic adenocarcinoma on histology slides

Pancreatic ductal adenocarcinoma (PAC) is a highly heterogeneous and plastic tumor with different transcriptomic molecular subtypes that hold great prognostic and theranostic values. We developed PACpAInt, a multistep approach using deep learning models to determine tumor cell type and their molecular phenotype on routine histological preparation at a resolution enabling to decipher complete intratumor heterogeneity on a massive scale never achieved before. PACpAInt effectively identified molecular subtypes at the slide level in three validation cohorts and had an independent prognostic value. It identified an interslide heterogeneity within a case in 39% of tumors that impacted survival. Diving at the cell level, PACpAInt identified "pure" classical and basal-like main subtypes as well as an intermediary phenotype and hybrid tumors that co-carried both classical and basal-like phenotypes. These novel artificial intelligence-based subtypes, together with the proportion of basal-like cells within a tumor had a strong prognostic impact.

cancer biology↗

bioRxiv2021

Cytolysin-positive Enterococcus faecalis is elevated in patients with chronic alcoholic pancreatitis

IntroductionPatients with alcoholic hepatitis have an increase in cytolysin-producing Enterococcus faecalis that correlates with disease severity and mortality. AimTo determine whether patients with chronic alcoholic pancreatitis have an elevated abundance of cytolysin-producing E. faecalis. MethodsQuantification by qPCR of cytolysin-producing E. faecalis in controls and patients with alcoholic hepatitis or pancreatitis. ResultsPatients with alcoholic pancreatitis had a higher proportion of intestinal cytolysin-positive E. faecalis than healthy controls and patients with alcoholic hepatitis. ConclusionCytolytic E. faecalis may also be involved in this other alcohol-related complication and benefit from targeted microbiota editing strategies.

physiology↗