Biology subjects

Bouchard, G.

Publications and source records attributed to Bouchard, G..

6 recordsLinked to original sources

bioRxiv2026

Genetic and Pharmacologic Targeting of Eya3 in Macrophages Drives Anti-Tumor Immunity in Triple-Negative Breast Cancer

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that remains difficult to treat despite its relatively high immunogenicity, as tumors frequently evade immune destruction through poorly understood mechanisms. Here, we discover a previously unrecognized role for Eya3 within macrophages in the tumor immune microenvironment, where its expression is elevated. Using macrophage Eya3 knockdown and conditional knockout models, we show that Eya3 depletion induces coordinated transcriptional and functional changes in macrophages, enhancing migration, antigen processing, and inflammatory signaling associated with anti-tumor immunity. Strikingly, macrophage-targeted deletion of Eya3 reprograms the immune response in TNBC, increasing CD8+ T cell infiltration, suppressing primary tumor growth, and prolonging survival. Pharmacologic inhibition of Eya3 tyrosine phosphatase activity with a novel allosteric inhibitor, LG1-34, mirrors this effect, dramatically reducing primary TNBC growth through immune-mediated mechanisms that likely act both though targeting tumor and immune cells. These findings identify Eya3 as a macrophage-intrinsic checkpoint on anti-tumor immunity, identifying a new potential vulnerability in TNBC. Significance StatementTargeting Eya3 tyrosine phosphatase activity in tumor-associated macrophages reprograms the TNBC immune microenvironment and restores anti-tumor immunity, identifying a new potential therapeutic vulnerability in a cancer that has limited treatment targeted options.

cancer biology↗

bioRxiv2023

Maternal body condition affects the response of the gut microbiome to a widespread contaminant in larval spined toads

Glyphosates primary metabolite, aminomethylphosphonic acid (AMPA), is the most detected pollutant in surface waters. Recent studies have raised concerns about its toxicity, yet underlying mechanisms remain poorly understood. A disruption of the gut microbiome, which plays a crucial role in host health, could mediate most of the adverse effects. We investigated the impact of AMPA exposure on the gut microbiome of spined toad tadpoles (Bufo spinosus). We hypothesized that AMPA could alter the gut microbiota composition and that these effects could depend on the microbiota source. We exposed tadpoles to minute concentrations of AMPA and analyzed their faecal microbiota using 16S rRNA gene sequencing as a proxy of the gut microbiota. AMPA exposure decreased the gut bacterial biomass and affected the bacterial community composition of tadpoles faeces. Furthermore, we observed interactions between AMPA exposure and maternal body condition on the Bacteroidota and Actinobacteriota phyla abundances. This suggests a maternal effect on early-life microbial colonizers that could influence the response of the gut microbiome to AMPA. These findings highlight the importance of considering the gut microbiome when studying the effects of environmental contaminants. Further research is needed to elucidate the long-term implications of this microbiome alteration for amphibian health.

ecology↗

bioRxiv2023

The colocatome as a spatial -omic reveals shared microenvironment features between tumour-stroma assembloids and lung cancer specimens

Computational frameworks to quantify and compare microenvironment spatial features of in-vitro patient-derived models and clinical specimens are needed. Here, we acquired and analysed multiplexed immunofluorescence images of human lung adenocarcinoma (LUAD) alongside tumour- stroma assembloids constructed with organoids and fibroblasts harvested from the leading edge (Tumour-Adjacent Fibroblasts;TAFs) or core (Tumour Core Fibroblasts;TCFs) of human LUAD. We introduce the concept of the "colocatome" as a spatial -omic dimension to catalogue all proximate and distant colocalisations between malignant and fibroblast subpopulations in both the assembloids and clinical specimens. The colocatome expands upon the colocalisation quotient (CLQ) through a nomalisation strategy that involves permutation analysis and thereby allows comparisons of CLQs under different conditions. Using colocatome analysis, we report that both TAFs and TCFs protected cancer cells from targeted oncogene treatment by uniquely reorganising the tumour-stroma cytoarchitecture, rather than by promoting cellular heterogeneity or selection. Moreover, we show that the assembloids colocatome recapitulates the tumour-stroma cytoarchitecture defining the tumour microenvironment of LUAD clinical samples and thereby can serve as a functional spatial readout to guide translational discoveries. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/557278v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@a79aa3org.highwire.dtl.DTLVardef@199582forg.highwire.dtl.DTLVardef@6c7fb6org.highwire.dtl.DTLVardef@134a2aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Multi-Omics Analysis of Fibroblasts from the Invasive Tumor Edge Reveals that Tumor-Stroma Crosstalk Induces O-glycosylation of the CDK4-pRB Axis

The invasive leading edge represents a potential gateway for tumor invasion. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in the activation of key biological pathways depending on their location in the tumor (edge vs core). Here, we highlight phenotypic differences between Tumor-Adjacent-Fibroblasts (TAFs) from the invasive edge and Cancer-Associated Fibroblasts (CAFs) from the tumor core, established from human lung adenocarcinomas. We use an innovative multi-omics approach that includes genomics, proteomics and, O-glycoproteomics to characterize crosstalk between TAFs and cancer cells. Our analysis shows that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the CDK4-pRB axis in the stroma, and indirectly modulates pro-invasive features of cancer cells. In summary, aside from improving the efficacy of CDK4 inhibitors anti-cancer agents, the O-glycoproteome poses a new consideration for important biological processes involved in tumor-stroma crosstalk.

cancer biology↗

bioRxiv2021

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

ABSTRACTTranslocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 tRCC patients identified across multiple genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8 + tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

cancer biology↗

bioRxiv2020

Integrative Molecular Characterization of Sarcomatoid and Rhabdoid Renal Cell Carcinoma Reveals Determinants of Poor Prognosis and Response to Immune Checkpoint Inhibitors

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1-3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

cancer biology↗