Biology subjects

Gaillard, S.

Publications and source records attributed to Gaillard, S..

6 recordsLinked to original sources

bioRxiv2025

Inhibition of Glutamine Metabolism Suppresses Tumor Progression through Remodeling of the Macrophage Immune Microenvironment

BackgroundTargeting glutamine metabolism has emerged as a promising strategy in cancer therapy. However, several barriers, such as in vivo anti-tumor efficacy, drug toxicity, and safety, remain to be overcome to achieve clinical utility. Prior preclinical in vivo studies had generated encouraging data showing promises of cancer metabolism targeting drugs, although most were performed on immune-deficient murine models. It is being recognized that aside from tumor cells, normal cells such as immune cells in the tumor microenvironment may also utilize glutamine for maintaining physiological functions. To provide an in-depth view of glutamine antagonist (GLNi) treatment on the tumor immune microenvironment, the current study made several unique approaches. MethodFirst, to evaluate GLNi treatment modality that potentially involves immune cells, the study was performed on immunocompetent murine models of gynecological cancers. Second, to enhance safety and reduce potential off-target effects, we developed a GLNi prodrug, JHU083, which is bio-activated restrictively in cancer tissues. Third, to unbiasedly decode the response of single cells in the tumor microenvironment to GLNi treatment, single-cell RNA sequencing (scRNA-seq) was performed on cells prepared from tumors of the JHU083 or vehicle control-treated mice. ResultsIn both immunocompetent murine tumor models, we observed a significant anti-tumor efficacy, resulting in reduced tumor burden and impeded tumor progression. Similarly, in both tumor models, scRNA-seq revealed significantly impeded immunosuppressive M2-like macrophages by JHU083, while the treatment spared pro-inflammatory M1-like tumor macrophages. In many tumor microenvironment (TME) cells, JHU083 downregulated genes regulated by Myc and hypoxia. M2 macrophages greater sensitivity to glutamine antagonism when compared to M1 macrophages or monocytes was further validated on ex vivo cultures of bone marrow-derived macrophages. ConclusionOur findings support a converged mechanism of glutamine metabolism antagonists. JHU083 exerted its anti-tumor efficacy through not only direct targeting of glutamine-addicted cancer cells but also by suppressing glutamine-dependent M2 macrophages, leading to a shift in the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.

cancer biology↗

bioRxiv2023

Gut microbiota promotes pain chronicity in Myosin1A deficient male mice

Over the past decade, the gut microbiota has emerged as an important regulator of nervous systems health and disease states1. Yet, its contribution to the pathogenesis of chronic somatic pain remains poorly documented. Chronic pain is a heavily debilitating disease affecting more than 1.5 billion people worldwide that can manifest through a long-lasting hypersensitivity to mechanical and/or thermal stimulations2,3. Maladaptive responses of dorsal root ganglia (DRG) neurons and spinal cord (SC) interneurons to tissue injuries and also of non-neuronal cells including DRG macrophages and SC microglia are acknowledged as important drivers of sensory symptoms underlying chronic pain4,3,5-7. Recent evidence shows that signals from gut microbiota are required for the initiation of injury-induced sensory hypersensitivity, via the ability to interact with the immune system8-11. However, whether and how gut microbiota promotes pain chronicity remains unknown. Here, we report that male mice lacking Myosin1a (KO)12 raised under single genotype housing conditions (KO-SGH) are predisposed to develop chronic injury-induced mechanical pain. We demonstrate that this predisposition is caused by their dysbiotic gut microbiota, which sustains the immune response in the DRG following neuropathic injury. Parental antibiotic treatment modifies gut microbiota composition and completely rescues the injury-induced chronic pain and associated DRG inflammatory response in male KO-SGH offspring. Together, our data establish a causal relationship between a dysbiotic gut microbiota and the predisposition to injury-induced chronic pain.

neuroscience↗

bioRxiv2020

Acute neonatal oxytocin impacts hippocampal network development and restores adult social memory deficits in a mouse model of autism spectrum disorder.

Oxytocin is a master regulator of the social brain. In some animal models of autism, notably in Magel2 tm1.1Mus-deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms focusing on social memory performance. We showed that Magel2tm1.1Mus-deficient mice present a deficit in social memory and studied the hippocampal circuits underlying this memory. We showed a co-expression of Magel2 and oxytocin-receptor in the dentate gyrus and CA2/CA3 hippocampal regions. Then, we demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin-receptors and of somatostatin interneurons. We also revealed a delay in the GABAergic development sequence in Magel2tm1.1Mus-deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring neuronal alterations and social memory. Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin-administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders.

neuroscience↗

bioRxiv2019

KDM5 histone-demethylases contribute to replication stress response and tolerance.

KDM5A and KDM5B histone-demethylases are overexpressed in many cancers and have been involved in drug tolerance. Here, we describe that KDM5A, together with KDM5B, contribute to replication stress (RS) response and tolerance. First, they positively regulate RRM2, the regulatory subunit of Ribonucleotide Reductase. Second, they are required for optimal activation of Chk1, a major player of the intra-S phase checkpoint that protects cells from RS. This role in Chk1 activation is probably direct since KDM5A is enriched at ongoing replication forks and associates with both PCNA and Chk1. Because RRM2 is a major determinant of replication stress tolerance, we developed cells resistant to HU, and show that KDM5A/B proteins are required for both RRM2 overexpression and tolerance to HU, in a manner that is independent of their demethylase activity. Altogether, our results indicate that KDM5A/B are major players of RS management. They also show that drugs targeting the enzymatic activity of KDM5 proteins may not affect all cancer-related consequences of KDM5A/B overexpression.

cancer biology↗

bioRxiv2018

Morphofunctional deficits in the cerebral cortex of NeuroD2 mutant mice are associated with autism/schizophrenia-like behaviors

We identified seven families associating NEUROD2 pathogenic mutations with ASD and intellectual disability. To get insight into the pathophysiological mechanisms, we analyzed cortical development in Neurod2 KO mice. Cortical projection neurons (CPNs) over-migrated during embryogenesis, inducing abnormal thickness and laminar positioning of cortical layers. At juvenile ages, dendritic spine turnover and intrinsic excitability were increased in L5 CPNs. Differentially expressed genes in Neurod2 KO mice were enriched for voltage-gated ion channels, and the human orthologs of these genes were strongly associated with ASD. Furthermore, adult Neurod2 KO mice exhibited core ASD-like behavioral abnormalities. Finally, by generating Neurod2 conditional mutant mice we demonstrate that forebrain excitatory neuron-specific Neurod2 deletion recapitulates cellular and behavioral ASD phenotypes found in full KO mice. Our findings demonstrate crucial roles for Neurod2 in cortical development and function, whose alterations likely account for ASD and related symptoms in the newly defined NEUROD2 mutation syndrome.

neuroscience↗

bioRxiv2018

A high-quality sequence of Rosa chinensis to elucidate genome structure and ornamental traits

Rose is the worlds most important ornamental plant with economic, cultural and symbolic value. Roses are cultivated worldwide and sold as garden roses, cut flowers and potted plants. Rose has a complex genome with high heterozygosity and various ploidy levels. Our objectives were (i) to develop the first high-quality reference genome sequence for the genus Rosa by sequencing a doubled haploid, combining long and short read sequencing, and anchoring to a high-density genetic map and (ii) to study the genome structure and the genetic basis of major ornamental traits.\n\nWe produced a haploid rose line from R. chinensis Old Blush and generated the first rose genome sequence at the pseudo-molecule scale (512 Mbp with N50 of 3.4 Mb and L75 of 97). The sequence was validated using high-density diploid and tetraploid genetic maps. We delineated hallmark chromosomal features including the pericentromeric regions through annotation of TE families and positioned centromeric repeats using FISH. Genetic diversity was analysed by resequencing eight Rosa species. Combining genetic and genomic approaches, we identified potential genetic regulators of key ornamental traits, including prickle density and number of flower petals. A rose APETALA2 homologue is proposed to be the major regulator of petals number in rose. This reference sequence is an important resource for studying polyploidisation, meiosis and developmental processes as we demonstrated for flower and prickle development. This reference sequence will also accelerate breeding through the development of molecular markers linked to traits, the identification of the genes underlying them and the exploitation of synteny across Rosaceae.

genomics↗