Biology subjects

Gueron, G.

Publications and source records attributed to Gueron, G..

4 recordsLinked to original sources

bioRxiv2026

IFNγ at the crossroads of systemic protection and brain vulnerability to coronavirus infection

The COVID-19 pandemic, together with previous outbreaks caused by highly pathogenic coronaviruses, highlighted the importance of understanding the host determinants that influence pathogenesis, both to improve our understanding of disease mechanisms, and to strengthen preparedness for future outbreaks. In our previous work we demonstrated dysregulation of IFN{gamma} response genes in COVID-19 patients, associated with both age and viral burden, positioning IFN{gamma} as a key mediator of host defense against SARS-CoV-2. Here, we used a preclinical murine model of coronavirus infection based on murine hepatitis virus (MHV-A59), widely validated for studying SARS-CoV-2 pathogenesis, together with IFN{gamma} knockout (IFN{gamma}-KO) mice to investigate the role of this cytokine during infection. We performed a comprehensive morphological, biochemical, hematological and proteomic characterization of infected wild-type (WT) and IFN{gamma}-deficient mice. Plasma proteomics revealed impaired inflammatory and coagulation-related responses in IFN{gamma}-KO animals compared to WT controls. We found increased viral load and infectious particles in peripheral organs, including liver, spleen, heart and muscle in IFN{gamma}-KO mice, whereas these were significantly reduced in the brain. Region-specific analysis further demonstrated decreased viral load in the prefrontal cortex and hippocampus of IFN{gamma}-KO animals. Consistently, bioinformatics analysis of transcriptomics data of IFN{gamma}-treated primary neuron cultures, together with frontal cortex from human COVID-19 patients, revealed activation of neuroinflammatory and neurological disease-associated pathways, supporting a role for IFN{gamma} in driving brain inflammatory responses during coronavirus infection. Together, these findings reveal a dual role for IFN{gamma} during coronavirus infection: it is important for controlling systemic viral dissemination and limiting peripheral tissue damage, yet it may also promote viral susceptibility and exacerbated inflammatory responses in the brain. These results support IFN{gamma} modulation as a potential therapeutic strategy to prevent or mitigate neurological complications associated with COVID-19. Author SummaryViral infections are controlled by the immune system, but the same responses that protect the body can sometimes contribute to tissue damage and disease. We investigated how a key immune molecule, called Interferon Gamma, influences the outcome of Coronavirus infection in different parts of the body. Using a mouse model of Coronavirus infection with Interferon Gamma deficiency, we found that this molecule plays two opposing roles: it helps control the spread of the virus throughout the body, but it also increases vulnerability of the brain to infection and inflammation. When this immune signal was absent, animals showed higher amounts of virus in several peripheral organs but surprisingly had lower levels of virus in specific brain regions. We further found that this immune response was associated with changes in inflammation and neurological processes in human data. Our findings reveal that antiviral immunity is not always uniformly protective and that its effects depend on the tissue involved. Understanding this balance may help guide future approaches to reduce virus-associated complications while preserving the protective functions of the immune response.

microbiology↗

bioRxiv2026

STAG2 Maintains Chromatin Compartmentalization and Represses Regulatory Element Contact to Promote Oncogenic Signaling in Muscle Invasive Bladder Cancer

Contrary to other cancer types, stromal antigen 2 (STAG2) expression is associated with shorter survival and an invasive phenotype in muscle invasive bladder cancer (MIBC). As a cohesin complex component, STAG2 regulates genome organization and cell type-specific transcription, yet its mechanistic role in MIBC remains unclear. Here, we uncover mechanisms through which STAG2 coordinates chromatin architecture and gene regulation in MIBC. Modulation of STAG2 rewired chromatin architecture, altering chromatin contacts and compartmentalization, increasing promoter-enhancer interactions, and reducing short-ranged chromatin loops. At specific gene loci, we discovered that STAG2 has context-specific activating and repressive regulatory functions. At the STAG2-activated gene ABCA1, STAG2 maintained A-compartment chromatin and high levels of promoter acetylation, indicators of active transcription. STAG2 KO resulted in loss of promoter acetylation, a shift from A to B compartment chromatin, and increased occupancy of the co-repressor TRIM28, resulting in ABCA1 downregulation and diminished invasive potential. Conversely, at the STAG2-repressed gene SPOCK3, STAG2 KO resulted in B to A compartment switching, aberrant formation of chromatin loops, and SPOCK3 upregulation. Treatment with EZH2 inhibitor tazemetostat augmented STAG2-KO induced SPOCK3 upregulation, suggesting a collaborative role of STAG2 and EZH2 in repressing Polycomb Repressive Complex 2 (PRC2) target genes. Altogether, our results indicate that STAG2 plays a multifaceted role in regulating gene expression in bladder cancer that is dictated by the epigenetic and chromatin landscape of the cells. These findings identify STAG2-dependent vulnerabilities and provide a rationale for therapeutic targeting of chromatin regulators in MIBC.

Cancer Biology↗

bioRxiv2022

Integrative analysis of the MD Anderson Prostate Cancer Patient-Derived Xenograft Series (MDA PCa PDX)

Progress in understanding prostate cancer (PCa) metastasis and therapy resistance has been hampered by the lack of models, representative of the clinical spectrum and biologic complexity of the disease. Our laboratory is home to one of the largest worldwide repositories of PCa patient-derived xenografts (PDXs), the MDA PCa PDX series, a collection of clinically annotated PDXs reflecting the full spectrum of potentially lethal disease, that includes tumors that are not end stage and not castration-resistant PCa. We performed whole genome sequencing, targeted sequencing and RNA sequencing of 46 MDA PCa PDX models derived from biopsy and surgical specimens from 39 patients, selected in order to reflect the clinicopathological PCa subtypes (data available in cBioPortal). MDA PCa PDXs genomic characterization shows that the cohort recapitulates the mutational landscape found in PCa, highlighting the clinical relevance of these models. Interestingly and consistently with the clinic, certain models lack the typical PCa driver alterations, thus providing a suitable tool for discovery of novel drivers. Our cohort also includes PDXs derived from different areas of the same tumor and longitudinal samples, allowing to study disease heterogeneity and progression. Finally, we have developed a procedure to grow organoids from PDXs, thus providing a powerful in vitro platform that supports hypothesis generation, and testing of clinically relevant observations. Genomic and transcriptomic characterization of MDA PCa PDXs together with the ability to grow them as organoids for in vitro experimentation, provides a unique resource to address the existing clinical gap in PCa, helping to better understand mechanisms of response and resistance. One Sentence SummaryMDA PCa PDX series is a dynamic resource capturing the molecular landscape of prostate cancer; a platform for discovery and personalized medicine

cancer biology↗

bioRxiv2020

Following the footprints of variability during filopodia growth

Filopodia are actin-built finger-like dynamic structures that protrude from the cell cortex. These structures can sense the environment and play key roles in migration and cell-cell interactions. The growth-retraction cycle of filopodia is a complex process exquisitely regulated by intra- and extra-cellular cues, whose nature remains elusive. Filopodia present wide variation in length, lifetime and growth rate. Here, we investigate the features of filopodia patterns in fixed prostate cancer cells by confocal microscopy. Analysis of almost a thousand filopodia suggests the presence of two different populations: one characterized by a narrow distribution of lengths and the other with a much more variable pattern with very long filopodia. We explore a stochastic model of filopodia growth which takes into account diffusion and reactions involving actin and the regulatory proteins formin and capping, and retrograde flow. Interestingly, we found an inverse dependence between the filopodial length and the retrograde velocity. This result led us to propose that variations in the retrograde velocity could explain the experimental lengths observed for these tumor cells. In this sense, one population involves a wider range of retrograde velocities than the other population, and also includes low values of this velocity. It has been hypothesized that cells would be able to regulate retrograde flow as a mechanism to control filopodia length. Thus, we propound that the experimental filopodia pattern is the result of differential retrograde velocities originated from heterogeneous signaling due to cell-substrate interactions or prior cell-cell contacts.

biophysics↗