Biology subjects

Dominguez, M.

Publications and source records attributed to Dominguez, M..

13 recordsLinked to original sources

bioRxiv2026

Tumour rewires host tryptophan metabolism to promote organism-wide immune suppression

How tumour genotype reshapes systemic metabolism to drive immune tolerance and tumour progression remains unclear. Here, we show that Pten-deficient Drosophila tumours reprogram host tryptophan metabolism, triggering systemic and local changes in immune and stromal compartments to foster tolerance. Tumour-derived nitric oxide activates the kynurenine pathway in liver-like tissue, selectively increasing the 3-hydroxykynurenine (3-HK) branch. Host 3-HK promotes tumour progression and suppresses immune function via aryl hydrocarbon receptor (AhR) signalling. These results identify the kynurenine pathway as a central tumour-host nexus and reveal how tumour genotype creates immune vulnerabilities.

cancer biology↗

bioRxiv2026

SMART: A Somatic Mutation Annotation and Reporting Tool for cancer genomics

MotivationTranslational interpretation of somatic variants from targeted oncology panels is hampered by inconsistent transcript prioritisation and by the need for reproducible pipelines that natively integrate OncoKB-derived evidence for research purposes. ResultsWe present SMART (Somatic Mutation Annotation and Reporting Tool), a Dockerised pipeline that embeds OncoKB API-derived annotations, including therapeutic (L1-4), resistance (R1-R3), diagnostic (Dx1-3), prognostic (Px1-3) and FDA levels, directly into a VCF-based workflow. SMART combines this with VEP, CIViC, Cancer Hotspots, ClinVar, SpliceAI, REVEL, LOEUF and gnomAD, applies a unified three-tier transcript prioritisation (whitelist > MANE Select > VEP fallback), and produces three-tiered outputs for computational, bioinformatic and research interpretation. Validation against reference APIs showed full concordance across 804 field-level checks. Availability and ImplementationSource code and Docker image are freely available at https://github.com/WeTGI-colab/SMART under the MIT License. SMART is provided for research use only; use of SMART outputs for patient specific clinical reports, clinical decision-making, or other patient-facing purposes requires appropriate governance and all required third-party licensing, including any OncoKB licence required for patient report generation.

bioinformatics↗

bioRxiv2026

Dynamin 2–dependent endocytosis differentially regulates ligand and receptor contributions to Notch signaling during neural precursor cell fate determination

A critical event in the development of the highly structured cerebral cortex is the appropriate generation of differentiated daughter cell populations from asymmetric precursor cell divisions. Internalization of extracellular receptors and ligands in the process of endocytosis is key to the establishment of asymmetry. However, the detailed mechanisms mediating this exchange are incompletely understood. The dynamin family of membrane remodeling GTPases is considered critical for many forms of clathrin-mediated endocytosis (CME) but its role in brain development is unexplored. Here we found that dynamin 2 (Dnm2), a protein involved in CME through vesicle release from the plasma membrane, is essential for the maintenance of neural stem cells. Conditional deletion of Dnm2 leads to early exhaustion of neural precursor cells and premature neurogenesis, resulting in gross structural abnormalities, periventricular hemorrhaging and increased perinatal mortality. Notably, Notch ligands accumulate at the cell surface and cleaved NICD is reduced in neural stem cells, consistent with impaired ligand-mediated activation. In contrast, inhibition of CME in receptor-expressing cells increases cell autonomous Notch signaling, likely by promoting receptor accumulation at the plasma membrane. Further, dynamin 1, 2, and 3 can rescue loss of Dnm2 to different extents. Taken together, these findings reveal that Dnm2 is the essential isoform for physiological non-cell autonomous Notch-mediated neural stem cell maintenance, and that CME exerts fundamentally distinct roles in Notch signaling, promoting ligand activity while restricting receptor signaling through control of surface receptor abundance.

Developmental Biology↗

bioRxiv2026

Pharmacodynamic and stage-dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer s disease

Alzheimers disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid-{beta} (A{beta}) accumulation, neuroinflammation, and cognitive decline. We previously identified Secreted Frizzled-Related Protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD-like traits in mice. Here, we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an -SFRP1 monoclonal antibody (-SFRP1) in APP/PS1 mice. Pharmacokinetics and target engagement of -SFRP1 were assessed in different groups of APP/PS1 mice using biotinylated or 89Zr-labelled antibodies, with tissue distribution and -SFRP1 levels quantified by in-house ELISA or PET/CT. Therapeutic efficacy was evaluated by administering -SFRP1 or the SFRP1 inhibitor WAY-316606 at different stages of disease progression via retro-orbital injection, followed by analysis of AD-like pathology using ELISA and immunofluorescence assays followed by quantifications and statistical analysis. Using 89Zr-labelled antibodies, we show that intravenously administered -SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24-hour clearance. Treatment with -SFRP1 had no apparent systemic side effects, but its therapeutic efficacy against AD-like brain pathology was strongly dependent on disease stage. While early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality with time. Pharmacological inhibition of SFRP1 using a small-molecule inhibitor similarly failed to ameliorate pathology at intermediate stages. Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain-targeted delivery strategies.

neuroscience↗

bioRxiv2024

TIAM1 signaling drives prostatic budding and branching phenotypes and is a potential therapeutic target for BPH

Benign prostatic hyperplasia (BPH) is the most prevalent urologic disease in men aged over 50 years. However, the molecular mechanisms that drive BPH pathophysiology remain elusive. In this study, we integrated bioinformatic and experimental analyses of human BPH to identify TIAM1-RAC1 signaling pathway as a promising candidate for a molecular-based approach for BPH therapy. First, elevated TIAM1 expression in a BPH transcriptomic signature that was generated from the analysis of RNA-seq data from three independent BPH patient cohorts was validated at the protein level in a fourth patient cohort. Additional bioinformatic analyses of the BPH transcriptomic signature pointed to TIAM1-RAC1 pathway as the potential lead therapeutic pathway; and NSC23766 - a small molecule inhibitor of TIAM1 signaling - as a developmental lead compound for BPH therapy. Next, a proof-of-concept pharmacological approach of TIAM1-RAC1 inhibition in human prostatic cells using NSC23766 resulted in attenuated organoid budding and branching - a developmental program associated with prostatic nodule formation and BPH pathogenesis. Finally, shRNA-based genetic knock-down of TIAM1 in human prostatic cells led to a reduction in budding and branching phenotypes thereby phenocopying the effects of NSC23766. Together, our observations implicate elevated TIAM1 as a driver of budding and branching in BPH, and our studies pave the way for TIAM1-RAC1 based targeted approach for the treatment of the disease.

cell biology↗

bioRxiv2023

Identification of dialects and individuals of globally threatened Yellow Cardinals using neural networks

Audio-based analysis of bird songs has proven to be a valuable practice for the growth of knowledge in the fields of ethology and ecology. In recent years, machine learning techniques applied to audio field recordings of bird calls have yielded successful results in studying population distributions and identification of individuals for their monitoring in a variety of bird species. This offers promising possibilities in the study of social behavior, biodiversity, and conservation strategies for birds. In this work, we trained deep learning models, directly from the sonograms of audio field recordings, to investigate the statistical properties of vocalizations in the endangered Yellow Cardinal. To our knowledge, this is the first time that this approach has been applied to this threatened species. Our results indicate the presence of vocal signatures that reflect similarities in songs of individuals that inhabit the same region, determining dialects, but which also show differences between individuals. These differences can be exploited by a deep learning classifier to discriminate the bird identities through their songs. Models trained with data labeled by regions showed a good performance in the recognition of dialects with a mean accuracy of (0.84 +/-0.04) significantly higher than accuracy obtained by chance. Precision and recall values also reflected the classifiers ability to find alike vocal patterns in the songs of neighboring individuals. Models trained with data labeled by individuals showed an accuracy of (0.63 +/-0.03) significantly higher than that obtained by chance. However, the individual discrimination model showed greater confusion with neighboring individuals. This reflects a hierarchical structure in the characteristics of the Yellow Cardinals vocalization, where the intra-individual variability is lower than the inter-individual variability, but it is even lower than the variability obtained when individuals inhabit different regions, providing evidence of the existence of dialects. This reinforces the results of previous works but also offers an automated method for characterizing cultural units within the species. Along with genetic data, this method could help better define management units, thereby benefiting the success of reintroduction programmes of recovered individuals of Yellow Cardinal. Moreover, the novelty of individual discrimination using neural networks for the Yellow Cardinal, which has limited data availability, shows promise for non-invasive acoustic monitoring strategies with potentially relevant implications for its conservation.

ecology↗

bioRxiv2022

Neuroendocrine control of catch-up growth in Drosophila

Children and other vertebrate animals stunted due to malnutrition can compensate for this deficit by resuming growth at a higher-than-normal rate via a still ill-defined mechanism. High mortality and adverse effects later in life may offset the positive effects of catch-up growth. Here we report that the invertebrate Drosophila melanogaster also experiences catch-up growth following a period of starvation, and the relaxin receptor Lgr4 instigates this catch-up growth. Starved larvae compensate for weight loss by growing two or more times faster and starting maturation within the same time as the non-starved sibling by preventing a rise in insulin-like growth (IGF)-induced ecdysone under Lgr4 control. Our data reveal that catch-up growth is associated with a surge of insulin, not IGF, which may clarify how catch-up growth often leads to metabolic problems and obesity.

developmental biology↗

bioRxiv2022

A Mesp1-dependent developmental breakpoint in transcriptional and epigenomic specification of early cardiac precursors

Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.

developmental biology↗

bioRxiv2020

Fra1 is required for TGFβ1 induced collective invasion

Phenotypic heterogeneity promotes tumor evolution and confounds treatment. Minority subpopulations of trailblazer cells enhance the heterogeneity of invading populations by creating paths in extracellular matrix (ECM) that permit the invasion of phenotypically diverse siblings. The regulatory programs that induce a trailblazer state are poorly understood. Here, we define a new Tgf{beta} induced trailblazer population that is more aggressive than previously characterized Keratin 14 expressing trailblazer cells. Rather than triggering a binary switch to a single trailblazer state, Tgf{beta} induced multiple unique states that were distinguished by their expression of regulatory transcription factors, genes involved in ECM reorganization and capacity to initiate collective invasion. The integration of a parallel Egfr signaling program was necessary to induce pro-motility genes and could be targeted with clinically approved drugs to prevent trailblazer invasion. Surprisingly, Egfr pathway activity also had the collateral consequence of antagonizing the expression of a cohort of Tgf{beta} induced genes, including a subset involved in ECM remodeling. Together, our results reveal a new compromise mode of signal integration that promotes a trailblazer state and can be therapeutically targeted to prevent collective invasion.

cancer biology↗

bioRxiv2020

The impact of transposable elements on tomato diversity

Tomatoes come in a multitude of shapes and flavors despite a narrow genetic pool. Here, we leveraged whole-genome resequencing data available for 602 cultivated and wild accessions to determine the contribution of transposable elements (TEs) to tomato diversity. We identified 6,906 TE insertions polymorphisms (TIPs), which result from the mobilization of 337 distinct TE families. Most TIPs are low frequency variants and disproportionately located within or adjacent to genes involved in environmental response. In addition, we show that genic TE insertions tend to have strong transcriptional effects and can notably lead to the generation of multiple transcript isoforms. We also uncovered through genome-wide association studies (GWAS) ~180 TIPs associated with extreme variations in major agronomic traits or secondary metabolites. Importantly, these TIPs tend to affect loci that are distinct from those tagged by SNPs. Collectively, our findings suggest a unique and important role for TE mobilization in tomato diversification, with important implications for future breeding.

plant biology↗

bioRxiv2018

The Notch and EGFR signaling regulate caspase inhibitor Diap1 to match supply with intestinal demand

The regenerative activity of adult stem cells carries a high risk of cancer, particularly in highly renewable tissues. To guarantee that the correct organ size is attained and to cope with the continual risk of cancer, developing tissues often use programmed cell death (PCD) as an adaptive mechanism to cull excess and abnormal cells. Members of the family of Inhibitor of Apoptosis Proteins (IAPs) inhibit caspases and cell death and are often overexpressed in cancer. Here, we show that Diap1 is expressed in committed progenitor (enteroblast) cells in the adult Drosophila intestine. Blocking endogenous caspases uncovered that more than half of enteroblasts produced by intestinal stem cells (ISCs) are actively eliminated by apoptosis in the physiological intestine and also led to tumorigenesis. We find that antagonistic interplay between the Notch and EGFR signaling on Diap1 regulation governs the enteroblast cell death or survival decision via the conserved Klumpfuss/WT1-Lozenge/RUNX axis, which also regulates of differentiation plasticity of enteroblasts. These data provide new insights into how apoptosis drives adult tissue renewal and protection against tumors.

cell biology↗

bioRxiv2018

Infectious Entry of Merkel Cell Polyomavirus

Merkel Cell Polyomavirus (MCPyV) is a small, non-enveloped tumor virus associated with an aggressive form of skin cancer, the Merkel cell carcinoma (MCC). MCPyV infections are highly prevalent in the human population with MCPyV virions being continuously shed from human skin. However, the precise host cell tropism(s) of MCPyV remains unclear: MCPyV is able to replicate within a subset of dermal fibroblasts, but MCPyV DNA has also been detected in a variety of other tissues. However, MCPyV appears different from other polyomaviruses as it requires sulfated polysaccharides such as heparan sulfates and/or chondroitin sulfates for initial attachment. Like other polyomaviruses, MCPyV engages sialic acid as a (co-receptor). To explore the infectious entry process of MCPyV, we analyzed the cell biological determinants of MCPyV entry into A549 cells, a highly transducible lung carcinoma cell line, in comparison to well-studied simian virus 40 and a number of other viruses. Our results indicate that MCPyV enters cells via caveolar/lipid raft-mediated endocytosis but not macropinocytosis, clathrin-mediated endocytosis or glycosphingolipid-enriched carriers. The viruses internalized in small endocytic pits that led the virus to endosomes and from there to the endoplasmic reticulum (ER). Similar to other polyomaviruses, trafficking required microtubular transport, acidification of endosomes, and a functional redox environment. To our surprise, the virus was found to acquire a membrane envelope within endosomes, a phenomenon not reported for other viruses. Only minor amounts of viruses reached the ER, while the majority was retained in endosomal compartments suggesting that endosome-to-ER trafficking is a bottleneck during infectious entry.\n\nImportanceMCPyV is the first polyomavirus directly implicated in the development of an aggressive human cancer, the Merkel Cell Carcinoma (MCC). Although MCPyV is constantly shed from healthy skin, MCC incidence increases among aging and immunocompromised individuals. To date, the events connecting initial MCPyV infection and subsequent transformation still remain elusive. MCPyV differs from other known polyomaviruses concerning its cell tropism, entry receptor requirements, and infection kinetics. In this study, we examined the cellular requirements for endocytic entry as well as the subcellular localization of incoming virus particles. A thorough understanding of the determinants of the infectious entry pathway and the specific biological niche will benefit prevention of virus-derived cancers such as MCC.

microbiology↗

bioRxiv2017

Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation

Concurrent activating mutations of the Notch and PI3K/Akt signalling pathways cooperate in the induction of aggressive cancers. Unfortunately, direct targeting of any of these aberrant pathways can result in severe side effects due to their broad physiological roles in multiple organs. Here, using an unbiased chemical in vivo screen in Drosophila we identified compounds that suppress the activity of the pro-inflammatory enzymes, nitric oxide synthase (NOS) and lipoxygenase (LOX), capable to block oncogenic Notch-PI3K/Akt cooperation without unwanted side effects. Genetic inactivation of NOS and LOX signalling components mirrors the anti-tumorigenic effect of the hit compounds. We show that NOS activity and immunosuppression associated to inflammation facilitates Notch-mediated tumorigenesis. Our study reveals an unnoticed immune inflammatory process underlying Notch-PI3K/Akt tumours and exposes NOS as a druggable target for anti-cancer therapeutic development.

cancer biology↗