Biology subjects

Marques, F.

Publications and source records attributed to Marques, F..

6 recordsLinked to original sources

bioRxiv2026

CD24 Acts as an Evolutionarily Conserved Innate Immune Checkpoint in Colorectal Cancer

Checkpoint immunotherapy has transformed cancer treatment, yet current approaches targeting adaptive immunity benefit only a subset of patients, leaving innate immunity as a largely untapped therapeutic frontier. Here, we identify CD24 as an innate immune checkpoint that protects colorectal tumors from macrophage-mediated clearance through an evolutionarily conserved recognition mechanism. Using zebrafish xenografts of isogenic colorectal cancer (CRC) cell lines, SW480 and SW620, we show that high CD24 expression in SW620 correlates with an immune-evasive, macrophage-resistant phenotype. Loss of human CD24 dramatically sensitizes tumors to clearance in zebrafish, while pharmacological macrophage depletion abolishes this effect. Mechanistically, CD24 suppresses innate immunity in a multilayered fashion, by limiting myeloid recruitment, dampening TNF-driven macrophage inflammatory polarization, and blocking phagocytosis. Live imaging further revealed that CD24 constrains macrophages to a restrained, patrol-like state, and that its loss enables them to adopt a highly motile, tumor-directed, and functionally engaged state, characterized by increased fusion activity and myeloid intercellular interactions. We show that zebrafish macrophages respond to human CD24 despite extensive evolutionary divergence, and glycocalyx profiling revealed broad remodeling of the tumor cell surface upon CD24 loss, suggesting evolutionary conservation of sialic acid-dependent receptor recognition. Transcriptomic analyses identified the Siglec-like gene si:dkey-24p1.7 as a candidate zebrafish macrophage-expressed receptor mediating this response. Finally, analysis of TCGA CRC cohorts revealed that CD24 expression is a stage-dependent prognostic marker, underscoring the clinical relevance of this axis. Together, these findings establish CD24 as a critical orchestrator of innate immune evasion in CRC, while further validating zebrafish xenografts as a powerful platform for dissecting innate immuno-oncobiology in vivo.

cancer biology↗

bioRxiv2025

Multi-omics Profiling of the Lateral Ventricle Choroid Plexus Reveals Developmental Cellular Remodeling, Early Immune Gene Activation, and a Novel Epithelial Subtype

Healthy brain development and function highly depend on the choroid plexus. Temporal alterations in the cellular landscape and gene expression of choroid plexus cells can alter immune cell trafficking in the brain and cerebrospinal fluid composition, ultimately impacting brain dynamics. Here, we performed a comprehensive multi-omics analysis--including bulk and single-cell transcriptomics and epigenomics--of the lateral ventricle choroid plexus across early postnatal and adult stages in mice and rats. We uncovered striking changes in the choroid plexus cellular composition from neonatal to adult stages, accompanied by transcriptional remodeling of all main cell types. Immune cells were markedly increased in adulthood and immune cell profiling revealed an altered cell-type diversity through time. Surprisingly, we observed an early gene activation of host-defense genes in all choroid plexus main cell types, beginning in the neonatal period and progressively increasing into young adulthood. Moreover, some genes induced in epithelial cells in response to inflammation were found to be epigenetically primed, despite not being transcriptionally active. Epithelial cells exhibited subtype diversity and plasticity, with distinct gene expression programs and chromatin accessibility profiles emerging over time. Notably, we identified a novel epithelial cell subtype with unique gene markers suggesting a specialized function potentially linked to neuro-signaling. Ligand-receptor interaction analysis revealed a progressive remodeling of cellular crosstalk networks during choroid plexus maturation, suggesting dynamic intercellular signaling as the tissue develops. Our study offers a comprehensive atlas of transcriptional activity and chromatin accessibility in choroid plexus cells, providing a valuable resource to guide future efforts in targeting gene expression at the choroid plexus for therapeutical purposes.

neuroscience↗

bioRxiv2025

Interlocked transcription factor feedback loops maintain and restore touch sensation

The sense of touch relies on the continuous function of specialized mechanosensory circuits, but the underlying molecular mechanisms remain poorly understood. Here, we report that the conserved transcription factors (TFs) CFI-1 (ARID3) and EGL-5 (HOXA7) jointly maintain in adult C. elegans the molecular identity of two key interneuron types, securing information processing within a mechanosensory circuit. Toggling between normal and low levels of CFI-1 or EGL-5 in adults generated digital-like (ON/OFF) effects both on touch-evoked escape response and interneuron identity. Strikingly, reintroduction of CFI-1 following its prolonged depletion restored escape response defects. Mechanistically, we identified two network motifs, a double-positive CFI-1/EGL-5 feedback loop and positive CFI-1 autoregulation, which together "lock-in" the interneuron identity programs. We propose that these interlocked motifs not only maintain robust escape responses throughout life, but are also essential for the restorability of adult-onset touch defects. Altogether, this work illuminates the molecular principles that maintain adult neuron identity and circuit function, and offers biomedically relevant insights into the restorability of neuronal and behavioral defects caused by mutations or variation in TF-encoding genes.

developmental biology↗

bioRxiv2024

Maturation-informed synthetic Magnetic Resonance Images of the Developing Human Fetal Brain

Magnetic resonance imaging is a powerful modality to investigate abnormal developmental patterns in utero. However, since it is not the first-line diagnostic tool in this sensitive population, data remain scarce and heterogeneous between scanners and centers. In addressing the data scarcity issue while generating data representative of real fetal brain MRI, we proposed FaBiAN, a Fetal Brain magnetic resonance Acquisition Numerical phantom. Here, we present a novel synthetic dataset of 594 two-dimensional, low-resolution series of T2-weighted images corresponding to 78 developing human fetal brains between 20.0 and 34.8 weeks of gestational age. Data are generated with substantive improvements from the original FaBiAN to account for local heterogeneities within white matter tissues throughout maturation. These synthetic-yet-highly-realistic images cover both healthy and pathological development trajectories simulated with standard clinical settings and anatomically informed by the Fetal Tissue Annotations (FeTA) dataset. Two independent radiologists qualitatively assessed the realism of the simulated images. We also quantitatively demonstrate the simulated datas increased fidelity to real data compared to the previous FaBiAN version. The reuse potential of the proposed dataset was also evaluated in the context of automated fetal brain tissue segmentation. Besides, our dataset that combines images generated from various clinical scenarios has been made publicly available to support the continuous endeavor of the community to develop advanced post-processing methods aswell as cutting-edge artificial intelligence models.

bioinformatics↗

bioRxiv2024

Efficacy of auxin-inducible protein degradation in C. elegans tissues using different auxins and TIR1-expressing strains

The auxin-inducible degradation system has emerged as a powerful tool to deplete proteins of interest in cells and tissues of various model organisms, including C. elegans 2-5. Here, we present a detailed protocol to perform AID-driven spatiotemporal depletion of specific proteins in C. elegans tissues. First, we introduced the AID degron and a fluorescent reporter at two conserved proteins: (a) the transcription factor CFI-1 (human ARID3), which is expressed in the nucleus of multiple C. elegans neurons and head muscle cells 6,7, and (b) the broadly expressed translation initiation factor Y47D3A.21 (human DENR) that localizes in the cytoplasm. Second, we provide a step-by-step guide on how to generate C. elegans strains suitable for AID-mediated protein (CFI-1 and DENR) depletion. Third, we find that the degree of CFI-1 and DENR depletion in C. elegans tissues is comparable upon treatment with either natural auxin (indole-3-acetic acid (IAA) or a water-soluble synthetic auxin analog (K-NAA). Last, we compare the degree of AID-mediated CFI-1 depletion in C. elegans neurons when the transport inhibitor response 1 (TIR1), component of the SCF ubiquitin ligase complex, is provided in neurons or all somatic cells. Altogether, this protocol provides side-by-side comparisons of different auxins and TIR1-expressing lines. Such comparisons may benefit future studies of AID-mediated protein depletion in C. elegans. Graphical abstractImage provided as pdf (together with Figures). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/575916v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@adf68eorg.highwire.dtl.DTLVardef@1160cfcorg.highwire.dtl.DTLVardef@aeb593org.highwire.dtl.DTLVardef@12c63e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIEfficient protein depletion in C. elegans tissues upon treatment with either natural or synthetic auxins. C_LIO_LIPansomatic TIR1 expression leads to efficient depletion of CFI-1 and DENR. C_LIO_LIPanneuronal TIR1 expression leads to neuron-specific, yet variable CFI-1 depletion. C_LIO_LIThe AID system is compatible with fluorescence microscopy, Western blotting and behavioral assays. C_LI

developmental biology↗

bioRxiv2022

Control of neuronal terminal differentiation through cell context-dependent CFI-1/ARID3 functions

ARID3 transcription factors are expressed in the nervous system, but their functions and mechanisms of action are largely unknown. Here, we generated in vivo a genome-wide binding map for CFI-1, the sole C. elegans ARID3 ortholog. We identified 6,396 protein-coding genes as putative direct targets of CFI-1, most of which (77%) are expressed in post-mitotic neurons and encode terminal differentiation markers (e.g., neurotransmitter receptors, ion channels, neuropeptides). To gain mechanistic insights, we focused on two neuron types. In sensory neurons (IL2 class), CFI-1 exerts a dual role: it acts directly to activate, and indirectly to repress, distinct terminal differentiation genes. In motor neurons, however, CFI-1 acts directly as a repressor, continuously antagonizing three transcriptional activators (UNC-3/Ebf, LIN-39/Hox4-5, MAB-5/Hox6-8). By focusing on a glutamate receptor gene (glr-4/GRIK1), we found CFI-1 exerts its repressive activity through proximal binding to the glr-4 locus. Further, the core DNA binding domain of CFI-1 is partially required for glr-4 repression in motor neurons. Altogether, this study uncovers cell context-dependent mechanisms through which a single ARID3 protein controls the terminal differentiation of distinct neuron types.

developmental biology↗