Biology subjects

Herault, O.

Publications and source records attributed to Herault, O..

5 recordsLinked to original sources

bioRxiv2025

Pro-inflammatory role of granzyme K producing bystander CD8+ T cells in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of blood malignancies with a 5-year survival rate below 30%, highlighting the urgent need for more effective therapeutic strategies. T cell-based immunotherapies have demonstrated remarkable success in solid tumors, yet the role of CD8+ T cells in AML remains unclear. In this study, we analyzed the composition, antigenic specificity, and function of CD8+ T cells in paired blood and bone marrow samples from AML patients. While we did not identify exhausted CD8+ T cells as seen in solid tumors, we observed a distinct population of functional CD69+ CD8+ T cells specifically enriched in the bone marrow. These cells primarily recognized non-tumor antigens, including epitopes derived from Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Notably, this bystander CD8+ T cell population showed high expression of Granzyme K, a cytokine found in the bone marrow of AML patients. Granzyme K did not induce leukemic cell death but instead promoted the secretion of IL-8, a pro-inflammatory cytokine known to play a detrimental role in AML pathology. Rather than mounting an anti-tumor response, these CD8+ T cells contribute to a pro-inflammatory environment that may exacerbate AML progression and severity. These findings provide a rationale for exploring therapeutic strategies aimed at inhibiting pro-inflammatory CD8+ T cells and targeting Granzyme K activity in association with actual therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/669682v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1fc9798org.highwire.dtl.DTLVardef@4491b1org.highwire.dtl.DTLVardef@1b8feadorg.highwire.dtl.DTLVardef@58515d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

scFv intrabody targeting wildtype TDP-43 presents protective effects in a cellular model of TDP-43 proteinopathy

TDP-43 proteinopathies are a set of neurological disorders characterized by the abnormal accumulation and mislocalization of TDP-43 in the cytoplasm, leading to the disruption of the normal function of the protein. In most of the cases, it is the wildtype (wt) form of the protein that is involved. An untargeted high-throughput screen of a single-chain variable fragment (scFv) library was performed using phage display against human full-length wt TDP-43. Two scFvs (B1 and D7) were retained following cellular expression (then termed intrabodies) and colocalization with cytoplasmic TDP-43 in vitro. We generated a 3D structure of full length wt TDP-43 in silico, and used it for epitope mapping. In a cellular model of TDP-43 proteinopathy, D7 enhanced the proteasomal degradation of the insoluble 35-kDa C-terminal fragment TDP-43 and reversed some TDP-43-induced metabolomic alterations, particularly relating to the lipid metabolism. Our findings offer a new scFv intrabody that bind to human wtTDP-43 and modify cellular pathways associated with TDP-43 proteinopathies.

neuroscience↗

bioRxiv2023

Encoding of the colorectal cancer metabolic program through MICU2

The mitochondrial Ca2+ uniporter (MCU) plays crucial role in intramitochondrial Ca2+ uptake, allowing Ca2+-dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and migration using in vitro and in vivo models of colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming. HighlightsO_LIMICU2 plays a pivotal role in the balance between anaerobic glycolysis and oxidative phosphorylation C_LIO_LIMICU2 stabilizes the mitochondrial network and endoplasmic reticulum-mitochondrial calcium flux C_LIO_LIMICU2 expression and the MICU2/MICU1 ratio control proliferation and metastasis formation in colorectal cancer C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/564893v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@6bb307org.highwire.dtl.DTLVardef@b6a966org.highwire.dtl.DTLVardef@2ba053org.highwire.dtl.DTLVardef@2ab691_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Low concentrations of ethylene bisdithiocarbamate pesticides maneb and mancozeb impair manganese and zinc homeostasis to induce oxidative stress and caspase-dependent apoptosis in human hepatocytes

The worldwide and intensive use of phytosanitary compounds results in environmental and food contamination by chemical residues. Human exposure to multiple pesticide residues is a major health issue. Considering that the liver is not only the main organ for metabolizing pesticides but also a major target of toxicities induced by xenobiotics, we studied the effects of a mixture of 7 pesticides (chlorpyrifos-ethyl, dimethoate, diazinon, iprodione, imazalil, maneb, mancozeb) often detected in food samples. Effects of the mixture was investigated using metabolically competent HepaRG cells and human hepatocytes in primary culture. We report the strong cytotoxicity of the pesticide mixture towards hepatocytes-like HepaRG cells and human hepatocytes upon acute and chronic exposures at low concentrations extrapolated from the Acceptable Daily Intake (ADI) of each compound. Unexpectedly, we demonstrated that the manganese (Mn)-containing dithiocarbamates (DTCs) maneb and mancozeb were solely responsible for the cytotoxicity induced by the mixture. The mechanism of cell death involved the induction of oxidative stress, which led to cell death by intrinsic apoptosis involving caspases 3 and 9. Importantly, this cytotoxic effect was found only in cells metabolizing these pesticides. Herein, we unveil a novel mechanism of toxicity of the Mn-containing DTCs maneb and mancozeb through their metabolization in hepatocytes generating the main metabolite ethylene thiourea (ETU) and the release of Mn leading to intracellular Mn overload and depletion in zinc (Zn). Alteration of the Mn and Zn homeostasis provokes the oxidative stress and the induction of apoptosis, which can be prevented by Zn supplementation. Our data demonstrate the hepatotoxicity of Mn-containing fungicides at very low doses and unveil their adverse effect in disrupting Mn and Zn homeostasis and triggering oxidative stress in human hepatocytes.

pharmacology and toxicology↗

bioRxiv2022

Curcumin and NCLX Inhibitors Share Anti-Tumoral Mechanisms in Microsatellite-Instability-Driven Colorectal Cancer

Colorectal cancer (CRC) is associated with high mortality worldwide and new targets are needed to overcome treatment resistance. Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of CRC. In this context, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new potential inhibitor of NCLX. In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis through mitochondrial permeability transition pore opening concomitant with G2/M cell cycle arrest. NCLX inhibition with either CGP37157 (a benzodiazepine derivative), small interfering RNA-mediated knock-down or knockout approaches reproduced the effects of curcumin. Altered mitochondrial respiration, cellular aerobic glycolysis and endoplasmic reticulum-mitochondria membrane perturbations participated in these mechanisms. In a xenograft mouse model, NCLX inhibitors decreased CRC tumor growth. Both transcriptomic analysis of The Cancer Genome Atlas dataset and immunohistochemical analysis of tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC demonstrated that higher NCLX expression was associated with MSI status and for the first time NCLX expression was significantly associated with recurrence-free survival in MSI CRC patients. Our findings provide strong evidence that blocking NCLX inhibits CRC in vitro and in vivo. We highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic treatment of patients with MSI CRC.

cancer biology↗