Biology subjects

Moreaux, J.

Publications and source records attributed to Moreaux, J..

10 recordsLinked to original sources

bioRxiv2026

ALDH Activity in Monocytes is Associated with Subclinical Coronary Atherosclerosis in Treated People with HIV-1

People living with HIV-1 (PWH) receiving antiretroviral therapy (ART) exhibit an increased cardiovascular disease (CVD) risk. Coronary atherosclerotic plaque formation is linked to chronic immune activation, a process fueled in PWH by additional mechanisms likely including residual HIV-1 production and microbial translocation from the gut during ART. Our previous studies demonstrated that aldehyde dehydrogenase (ALDH), an enzyme converting vitamin A into retinoic acid (RA), is upregulated in myeloid cells upon exposure to viral/bacterial/fungal products and that RA promotes HIV-1 production. To explore the link between ALDH/RA pathway and CVD risk, we used PBMC/plasma from ART-treated PWH (PWH+ART; n=51) and people without HIV-1 (Pw/oH; n=63) from the Canadian HIV/Aging Cohort Study, with/without subclinical coronary atherosclerosis, measured by coronary computed tomography angiography. ALDH expression was analyzed by flow cytometry on monocyte subsets, dendritic cells, and CD4+ T-cells. Unsupervised t-SNE-guided FlowSOM analysis associated top ALDH activity with a monocyte phenotype. The frequency of ALDH+ monocytes and plasma levels of RA and retinol binding protein 4 were increased in PWH+ART versus Pw/oH, with the highest RA levels coinciding with detectable plasma levels of soluble HIV-1 gp120. Multivariate regression models linked ALDH activity in monocytes to subclinical coronary atherosclerosis (i.e., total plaque volume, low attenuated plaque volume, coronary artery calcification score) presence/burden in PWH+ART, independently of Framingham risk score. Finally, ALDH+ monocyte frequency and RA levels positively correlated with pericoronary fat attenuation index, an emerging CVD predictor. Thus, ALDH/RA pathway may represent a new marker of metabolic/immune dysfunction contributing to CVD risk in ART-treated PWH.

immunology↗

bioRxiv2026

REV-ERBα/β Targeting Transcriptionally Reprograms HIV-Infected CD4+ T-Cells for Increased Viral Reactivation but Limited Virion Spread

The circadian clock repressors REV-ERB/{beta} control rhythmic gene expression and inhibit HIV-1 transcription. Whether REV-ERB/{beta} modulate the HIV-1 replication cycle beyond transcription remains unknown. Here, we demonstrate that memory CD4+ T-cells predominantly express the REV-ERB{beta} isoform ex vivo and that T-cell receptor (TCR) triggering downregulates both REV-ERB/{beta} expression, with levels of REV-ERB/{beta} mRNA being lower in ART-treated people with HIV (PWH) receiving antiretroviral therapy (ART) compared to people without HIV (PWoH) before/after TCR triggering. In single-round infection, the REV-ERB/{beta} antagonist SR8278 facilitated HIV-1 reverse transcription, integration, and intracellular HIV-p24 expression, but limited virion release. Moreover, SR8278 downregulated CCR5 mRNA expression, inhibited R5-tropic HIV-1 replication in vitro, and limited viral outgrowth in CD4+ T-cells from ART-treated PWH. Finally, genome-wide RNA-sequencing and functional validations revealed HIV-1 restriction/dependency factors that represent novel putative REV-ERB/{beta} targets. Thus, pharmacological inhibition of REV-ERB/{beta} uniquely combines a latency reversal activity with the inhibition of progeny virion spread.

immunology↗

bioRxiv2024

Single-Nuclei Analysis of the Unfolded Protein Response (SNUPR): A Novel Method revealing bortezomib resistance mechanisms in Multiple Myeloma

AbstractThe unfolded protein response (UPR) is a key stress resistance pathway that has become a key potential target for improving the efficacy of cancer chemotherapy. The UPR involves the activation of three ER-resident stress sensors: PERK, IRE-1 and ATF6 with different signalling outcomes leading to cell death or survival. These cell-fate decisions are difficult to predict and are the result of the complex interaction of PERK, IRE-1 and ATF6 downstream events that have differences in their dynamics and their interplay. These characteristics of the UPR are still poorly defined due to lack of methods to monitor their activation simultaneously at single-cell level. We developed SNUPR (Single Nuclei analysis of the Unfolded Protein Response), an accessible technique that allows the profiling of the three UPR branches in nuclear suspensions by flow cytometry, and applied it to study UPR dynamics in a cancer-specific context. By performing transcriptomic analysis, we found that ER-stress sensor specific gene signatures correlate with patient survival in several blood malignancies, and by using SNUPR, we detected high heterogeneity during UPR activation in vitro in different human cancer cell lines, which could not be have been predicted by the level of expression of the sensors. Our SNUPR analyses further indicate that this heterogeneity is explained by variations in the intensity and duration of ER stress-induced protein synthesis inhibition via PERK, acting as upstream regulator of both the IRE-1/XBP1 and ATF6 dependent transcriptional programs. We extend the relevance of these observations by demonstrating that IRE-1/XBP1s pathway plays a critical role in bortezomib resistance of multiple myeloma cells and patients. We present here SNUPR, that can be used to monitor UPR dynamics with single-cell resolution and identified clinical contexts in which targeting a specific UPR branch could be detrimental or help circumventing chemotherapy resistance. One Sentence SummarySNUPR method enable single-cell UPR profiling and reveals the role of IRE-1 axis in predicting bortezomib resistance in multiple myeloma. HighlightsO_LISNUPR allows simultaneous profiling of PERK, IRE-1 and ATF6 activation with single- cell resolution. C_LIO_LIInhibition of protein synthesis via PERK control the activation levels of the IRE-1/XBP1s and ATF6 pathway. C_LIO_LIIRE-1 activation and associated transcriptional signatures predict the outcome of patients with multiple myeloma treated with Bortezomib. C_LIO_LIIRE-1 activity, but not PERK or ATF6, is essential to acquire bortezomib resistance in multiple myeloma cell lines. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/617161v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@297668org.highwire.dtl.DTLVardef@1cab0eorg.highwire.dtl.DTLVardef@2238b4org.highwire.dtl.DTLVardef@b8ebf6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

A non-catalytic function for Rad18 in sustaining glioblastoma proliferation

The Rad18 E3 ubiquitin ligase, a non-essential gene, is a key regulator of DNA damage tolerance that also functions in repair of DNA double strand breaks. Rad18 is overexpressed in the aggressive brain cancer glioblastoma (GBM) and its downregulation sensitizes glioblastoma cells to DNA damaging agents. Here we show that Rad18 has an essential role in GBM cells proliferation in the absence of external damage, surprisingly independent of its catalytic activity. Rad18 downregulation leads to cell cycle arrest in the G1 phase in the absence of apparent DNA damage. We also show that Rad18 sustains GBM stem cells self-renewal and survival, as well as the growth of tumor orthotropic xenografts in mice. We also show that increased Rad18 expression enhances the growth of non-transformed cells and induces features of oncogenic transformation. Mechanistically, we show that Rad18 downregulation negatively regulates the Hippo pathway by interfering with the nuclear retention of the YAP1 transcription factor. Altogether, these data show that Rad18 has an essential, non-catalytic function, in GBM proliferation, and propose Rad18 as a key target to sensitize GBM to therapy.

cancer biology↗

bioRxiv2023

Transient loss of Polycomb components induces an epigenetic cancer fate

Cell fate depends on genetic, epigenetic and environmental inputs that are interconnected, making it difficult to disentangle their respective contributions to cell fate decisions1-3, and epigenetic reprogramming is a major contributor to tumor plasticity and adaptation4-6. Although cancer initiation and progression are generally associated with the accumulation of somatic mutations7,8, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility9-18, suggesting that genetic mechanisms alone may not be sufficient to drive malignant transformations19-23. However, whether purely non-genetic reprogramming mechanisms are sufficient to initiate tumorigenesis irrespective of mutations is unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb-Group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including JNK and JAK-STAT signalling pathways and zfh1, the fly homolog of the ZEB1 oncogene, which we show to be a necessary driver of the cancer fate. These data show that a reversible perturbation of Polycomb-Group protein levels can induce cancer in the absence of driver mutations and suggest that this is achieved through epigenetic inheritance of altered cell fates.

developmental biology↗

bioRxiv2022

Var I Decrypt: a novel and user-friendly tool to explore and prioritize variants in whole-exome sequencing data

MotivationHigh throughput sequencing (HTS) offers unprecedented opportunities for the discovery of causative gene variants in multiple human disorders including cancers, and has revolutionized clinical diagnostics. However, despite more than a decade of use of HTS-based assays, extracting relevant functional information from whole exome sequencing (WES) data remains challenging, especially for non-specialists lacking in-depth bioinformatic skills. ResultsTo address this limitation, we developed Var|Decrypt, a web-based tool designed to greatly facilitate WES data browsing and analysis. Var|Decrypt offers a wide range of gene and variant filtering possibilities, clustering and enrichment tools, providing an efficient way to derive patient-specific functional information and to prioritize gene variants for functional analyses. We applied Var|Decrypt on WES datasets of 10 acute erythroid leukemia patients, a rare and aggressive form of leukemia, and recovered known disease oncogenes in addition to novel putative drivers. We additionally benchmarked Var|Decrypt on an independent dataset of ~90 multiple myeloma WES, recapitulating the identified deregulated genes and pathways, showing the general applicability and versatility of Var|Decrypt for WES analysis.

bioinformatics↗

bioRxiv2022

Single-hit genome edition for expression of single-chain immunoglobulins by edited B cells

Lymphocytes have become attractive agents for adoptive immunotherapy but only the reformatting of T cells is efficiently mastered. Despite some recent breakthroughs, B cells remain challenging targets, with regard to both their long-term survival after in vitro manipulation and the rewiring of immunoglobulin (Ig) expression. Working on these two aspects, we have designed a new format of single-chain Ig ("scFull-Ig") coding cassette, the insertion of which at a single genomic position can redirect B cells toward a new antigen specificity, while preserving all functional domains of the B cell receptor. Precise genomic edition at a single locus then provides the most efficient and safe strategy to both disrupt endogenous Ig expression while encoding a new Ig paratope. As proofs of concept, functionality of such scFull BCR was validated by checking specific binding of two different classical targets of tumor immunotherapy, HER2 and CD20. Once the strategy validated in cell lines, it was also validated in primary B cells, again showing successful engineering of BCR expression. These results contribute to pave the way for future B cell-based adoptive cell therapy.

immunology↗

bioRxiv2021

The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of Acute Myeloid Leukemias

Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase activity, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. In addition, analyzing gp91phox (CYBB-encoded Nox2 catalytic sub-unit) expression at the surface of leukemic blasts from 74 patients at diagnosis showed that NOX2 is generally more expressed and active in leukemic cells from the FAB M4/M5 subtypes compared to FAB M0-M2 ones. Using a gene expression-based score we demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis, independent of the cytogenetic-based risk classification, in AML patients.

cancer biology↗

bioRxiv2019

Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. Here we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for histone H4K20 mono-methylation, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Remarkably, primary malignant plasma cells are particularly addicted to SETD8 activity. Indeed, pharmacological inhibition of this enzyme by the chemical compound UNC0379 demonstrated a significantly higher toxicity in MM cells compared to normal cells from the bone marrow microenvironment. Moreover, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and an activation of the p53 canonical pathway, which together leads to an impairment of myeloma cell proliferation and survival. However, UNC0379 treatment triggers a deadly level of replicative stress in p53 deficient MM cells, indicating that the cytotoxicity associated with SETD8 inhibition is independent of the p53 status. Consistent with this, the combination of UNC0379 with the conventional cytotoxic agent melphalan strongly enhances DNA damage and overcomes drug resistance in myeloma cells. Thus, targeting SETD8 could be of therapeutic interest to improve MM treatment in high-risk patients independently of the p53 status.

cancer biology↗

bioRxiv2018

Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.

Metabolic alterations support cellular transformation. Noticeably, cellular transformation and cancer progression is associated with accumulation of dihydrouracil and dihydrothymine. However, it remains elusive how dihydropyrimidine metabolites affect cellular phenotypes. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP). This zinc metalloenzyme is upregulated in solid tumors but not in the corresponding normal tissues. Here we show that DHP silencing in transformed cell lines is cytotoxic. Increasing the level of dihydropyrimidines inhibited DNA replication and transcription. It induced replication stress signaling by ATR and p53 stabilization. Remarkably, cells lacking DHP accumulated DNA-protein crosslinks (DPCs). Among DPCs, covalently trapped translesion DNA polymerase {eta} contributed to the cytotoxicity of dihydropyrimidines. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits the activity of recombinant human DHP. Cellular treatment with dihydromyricetin triggered DPCs-dependent DNA replication stress. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.

cancer biology↗