Biology subjects

Bournet, B.

Publications and source records attributed to Bournet, B..

4 recordsLinked to original sources

bioRxiv2024

Regenerative potential of human enteric glia in a preclinical model of acute brain injury

BackgroundAcute brain injury is characterized by extensive tissue damage, resulting in neuronal loss and functional deficits in patients. The capacity of nerve tissue to self-regenerate is insufficient to repair damaged tissue, thus therapies based on exogenous cells are urgently needed. Human enteric glia (EG) have interesting intrinsic properties that make them a valuable candidate for regenerative medicine. In this long-term study, we investigated whether human EG treatment induces tissue repair and improves functional recovery in a rat model of brain injury. MethodsAcute brain injury was induced by malonate injection in the motor cortex of female rats, causing extensive tissue damage and long-lasting sensorimotor deficits. Human EG were isolated from gut tissue, expanded and administered intranasally in awake immunocompetent rats. To determine the long-term safety and efficacy of human EG treatment, longitudinal evaluation of sensorimotor function, post-mortem tissue regeneration and the fate of human EG were assessed thirty-six weeks after intranasal administration. ResultsTransplanted human EG satisfied the safety criteria, non-immunogenic and non-tumorigenic, required for cell therapy; they were well tolerated in immunocompetent rats, and induced sensorimotor improvement. Importantly, thirty-six weeks post-treatment, intranasally delivered human EG were detected in the rat brain, mainly in the injured motor cortex. This indicated that transplanted human EG migrated and successfully engrafted and integrated with the host tissue. Additionally, human EG induced tissue regeneration by enhancing endogenous angiogenesis and neurogenesis. Notably, thirty-six weeks after administration, human EG generated mature neurons that were enveloped by oligodendrocytes and formed synaptic connections with the host tissue. ConclusionsTransplanted human EG induced tissue repair and showed regenerative potential after brain injury. This is the first study demonstrating the feasibility, safety and efficacy of intranasal administration of human EG for treatment of brain injury.

neuroscience↗

bioRxiv2024

Pathogenicity of Commensal Gut Biofilm In Prefrail Aging

Pathophysiological mechanisms of unhealthy aging, particularly the transition from robustness to frailty, remain poorly understood. Despite extensive microbiome research on taxonomy, the behavior of early prefrail gut bacteria in their natural community-host mucosal tissue context remains unexplored. Using fecal samples from the INSPIRE-T aging human cohort, we characterized gut microbiota phenotype during prefrailty stages using a polymicrobial biofilm model. Results revealed that prefrail-derived biofilms exhibited distinct taxonomic and physical alterations, enhanced dispersal, and increased epithelial virulence compared to robust counterparts. Multiparametric analyses linked biofilm characteristics to clinical traits, suggesting their potential as aging status indicators. Polyphenol-rich grape pomace extract partially reversed prefrail biofilm alterations and reduced proinflammatory prefrail biofilm responses in vitro. Microbiota from prefrail aged mice induced colon damage in antibiotic-treated recipients, establishing a prefrail microbiome-inflammation causality. Overall, the findings identified novel prefrail microbiome characteristics, established causal inflammatory links, and support microbiota-targeted geroprotective interventions for the prefrail populations.

microbiology↗

bioRxiv2020

Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We researched a gene signature that could discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3K activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3K-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3K inhibition altered the quantity and the species composition of the lipid second messenger PIP3 produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3K inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour-cell intrinsic PI3K therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution. The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood. RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3K activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3K is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3K activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3K is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K -selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3K activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3K delayed primary tumour and micro-metastasis evolution. Finally, PI3K activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution. IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3K-selective inhibitors significantly delay metastatic progression and death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/307884v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a5a8b4org.highwire.dtl.DTLVardef@1e6e18dorg.highwire.dtl.DTLVardef@e22859org.highwire.dtl.DTLVardef@1c7148b_HPS_FORMAT_FIGEXP M_FIG Pancreatic ductal adenocarcinoma requires tumour-intrinsic PI3K activity to accelerate inflammatory metastatic disease. Biorender illustration. C_FIG

cancer biology↗

bioRxiv2020

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

BACKGROUNDA significant gap in pancreatic ductal adenocarcinoma (PDAC) patients care is the lack of molecular parameters characterizing tumors and allowing a personalized treatment. The goal of this study was to examine whole PDAC transcriptomic profiles to define a signature that would predict aggressiveness and treatment responsiveness better than done until now. METHODS AND PATIENTSTumors were obtained from 76 consecutive resectable (n=40) or unresectable (n=36) tumors. PDAC were transplanted in mice to produce patient-drived xenografts (PDX). PDX were classified according to their histology into five groups, from highly undifferentiated to well differentiated. This classification resulted strongly associated with tumors aggressiveness. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n=598) of resected tumors; ii/ 60 advanced tumors obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumors. RESULTSA unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumors (e.g. 308 consecutive resected PDAC, HR=0.321 95% CI [0.207;0.5] and 60 locally-advanced or metastatic PDAC, HR=0.308 95% CI [0.113;0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumor response: -0.67, p-value < 0.001). CONCLUSIONWe identified a transcriptomic signature (PAMG) that, unlike all other stratification schemas already proposed, classifies PDAC along a continuous gradient. It can be performed on formalin-fixed paraffin-embedded samples and EUS-guided biopsies showing a strong prognostic value and predicting mFOLFIRINOX responsiveness. We think that PAMG could unify all PDAC preexisting classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient. Trial RegistrationThe PaCaOmics study is registered at www.clinicaltrials.gov with registration number NCT01692873. The validation BACAP study is registered at www.clinicaltrials.gov with registration number NCT02818829.

cancer biology↗