Biology subjects

Favreau, C.

Publications and source records attributed to Favreau, C..

8 recordsLinked to original sources

bioRxiv2025

Non-canonical caspase-8 activation by cathepsin B drives anti-inflammatory human macrophage polarization

Anti-inflammatory monocyte-derived macrophages are essential to maintain tissue homeostasis but can also contribute to disease progression, notably in cancer and fibrosis. Deciphering the signaling pathways that govern their generation could therefore unlock new therapeutic opportunities. Here we uncover a previously unrecognized, non-apoptotic function of caspase-8 in driving both monocyte-to-macrophage differentiation and anti-inflammatory macrophages polarization. We identified cathepsin B as a novel upstream activator of caspase-8 activation through a non-canonical cleavage mechanism, conferring to caspase-8 an original activity profile distinct from its apoptotic role. Disruption of this cathepsin-B-caspase-8 axis, either genetically or pharmacologically, not only impairs the generation of anti-inflammatory macrophages but also reprograms these cells towards a pro-inflammatory phenotype. Our findings position the cathepsin-B-caspase-8 axis as a critical regulatory node in macrophage fate decisions and a promising target for therapeutic reprogramming of human macrophages in cancer, inflammation and fibrotic diseases.

immunology↗

bioRxiv2024

Modeling of blood flow dynamics in the rat somatosensory cortex

The cerebral microvasculature forms a dense network of interconnected blood vessels where flow is modulated partly by astrocytes. Increased neuronal activity stimulates astrocytes to release vasoactive substances at the endfeet, altering the diameters of connected vessels. Our study simulated the coupling between blood flow variations and vessel diameter changes driven by astrocytic activity in the rat somatosensory cortex. We developed a framework with three key components: coupling between vasculature and synthesized astrocytic morphologies, a fluid dynamics model to compute flow in each vascular segment, and a stochastic process replicating the effect of astrocytic endfeet on vessel radii. The model was validated against experimental flow values from literature across cortical depths. We found that local vasodilation from astrocyte activity increased blood flow, especially in capillaries, exhibiting a layer-specific response in deeper cortical layers. Additionally, the highest blood flow variability occurred in capillaries, emphasizing their role in cerebral perfusion regulation. We discovered that astrocytic activity impacts blood flow dynamics in a localized, clustered manner, with most vascular segments influenced by two to three neighboring endfeet. These insights enhance our understanding of neurovascular coupling and guide future research on blood flow-related diseases.

neuroscience↗

bioRxiv2024

Dual targeting of GPX4 and TXNRD1 triggers eradication of AML cells through induction of apoptosis and ferroptosis

MyeloDysplastic Syndromes (MDS) are a group of heterogeneous hematological disorders characterized by bone marrow failure and abnormal hematopoietic cell expansion, often progressing to acute myeloid leukemia (AML). Current treatments for AML and high-risk MDS have limited efficacy, requiring the exploration of new therapeutic approaches. Recent research highlighted the potential of inducing cell death through ferroptosis, either independently or alongside traditional chemotherapy, as promising approaches for treating MDS/AML cells. We described here two novel compounds, HA344 and #231, capable of targeting both ferroptosis and apoptosis, leading to the effective eradication of cell lines and primary blasts from MDS/AML patients, while sparing normal hematopoietic cells. RNASeq analysis identified oxidation reduction and apoptotic processes as highly significant induced pathways in two different AML cell lines. Using click-chemistry approaches coupled to mass spectrometry, we identified glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1) as the main targets of HA344 and #231 in a large panel of AML cells. Accordingly, both compounds inhibited GPX4 and TXNRD1 activity in the micromolar range and triggered GPX4 degradation. Moreover, using recombinant GPX4 carrying or not a selenium (GPX4-Se and GPX4-S), we confirmed by mass spectrometry that HA344 and #231 bind more efficiently GPX4-Se than GPX4-S. In conclusion, these compounds might represent a new pharmacological approach in the treatment of MDS and AML, offering a potential avenue for future therapies.

biochemistry↗

bioRxiv2023

Community-based Reconstruction and Simulation of a Full-scale Model of Region CA1 of Rat Hippocampus

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to reconcile information obtained from diverse experimental approaches. To address this challenge, we present a community-driven, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to address a range of scientific questions. In this article, we describe the methods used to set up simulations that reproduce and extend in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce and reconcile experimental findings. Finally, we make data, code and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This neuroscience community-driven model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region.

neuroscience↗

bioRxiv2023

MCB-613 exploits a collateral sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer through covalent inhibition of KEAP1

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR-mutant NSCLC cells.

cancer biology↗

bioRxiv2022

Molecular Acclimation of Halobacterium salinarum to Halite Brine Inclusions

1Halophilic microorganisms have long been known to survive within the brine inclusions of salt crystals, as evidenced by the change in color for salt crystals containing pigmented halophiles. However, the molecular mechanisms allowing this survival has remained an open question for decades. While protocols for the surface sterilization of halite (NaCl) have enabled isolation of cells and DNA from within halite brine inclusions, "-omics" based approaches have faced two main technical challenges: (1) removal of all contaminating organic biomolecules (including proteins) from halite surfaces, and (2) performing selective biomolecule extractions directly from cells contained within halite brine inclusions with sufficient speed to avoid modifications in gene expression during extraction. In this study, we present methods to resolve these two technical challenges. In addition, we apply these methods to perform the first examination of the early acclimation of a model haloarchaeon (Halobacterium salinarum NRC-1) to halite brine inclusions. Examinations of the proteome of Halobacterium cells two months post-evaporation revealed a high degree of similarity with stationary phase liquid cultures, but with a sharp down-regulation of ribosomal proteins. Low quantities of RNA from halite brine inclusions corroborate the hypothesis of low transcriptional and translational activities. While proteins for central metabolism were part of the shared proteome between liquid cultures and halite brine inclusions, proteins involved in cell mobility (archaellum, gas vesicles) were either absent or less abundant in halite samples. Proteins unique to cells within brine inclusions included transporters, suggesting modified interactions between cells and the surrounding brine inclusion microenvironment. The methods and hypotheses presented here enable future studies of the survival of halophiles in both culture model and natural halite systems.

microbiology↗

bioRxiv2022

Modeling and Simulation of Rat Non-Barrel Somatosensory Cortex. Part I: Modeling Anatomy

The function of the neocortex is fundamentally determined by its repeating microcircuit motif, but also by its rich, interregional connectivity. We present a data-driven computational model of the anatomy of non-barrel primary somatosensory cortex of juvenile rat, integrating whole-brain scale data while providing cellular and subcellular specificity. The model consists of 4.2 million morphologically detailed neurons, placed in a digital brain atlas. They are connected by 14.2 billion synapses, comprising local, mid-range and extrinsic connectivity. We delineated the limits of determining connectivity from neuron morphology and placement, finding that it reproduces targeting by Sst+ neurons, but requires additional specificity to reproduce targeting by PV+ and VIP+ interneurons. Globally, connectivity was characterized by local clusters tied together through hub neurons in layer 5, demonstrating how local and interegional connectivity are complicit, inseparable networks. The model is suitable for simulation-based studies, and a 211,712 neuron subvolume is made openly available to the community.

neuroscience↗

bioRxiv2022

Reconstruction and simulation of thalamoreticular microcircuitry

Thalamoreticular circuitry is known to play a key role in attention, cognition and the generation of sleep spindles, and is implicated in numerous brain disorders, but the cellular and synaptic mechanisms remain intractable. Therefore, we developed the first detailed computational model of mouse thalamus and thalamic reticular nucleus microcircuitry that captures morphological and biophysical properties of [~]14,000 neurons connected via [~]6M synapses, and recreates biological synaptic and gap junction connectivity. Simulations recapitulate multiple independent network-level experimental findings across different brain states, providing a novel unifying cellular and synaptic account of spontaneous and evoked activity in both wakefulness and sleep. Furthermore, we found that: 1.) inhibitory rebound produces frequency-selective enhancement of thalamic responses during wakefulness, in addition to its role in spindle generation; 2.) thalamic interactions generate the characteristic waxing and waning of spindle oscillations; and 3.) changes in thalamic excitability (e.g. due to neuromodulation) control spindle frequency and occurrence. The model is openly available and provides a new tool to interpret spindle oscillations and test hypotheses of thalamoreticular circuit function and dysfunction across different network states in health and disease.

neuroscience↗