Biology subjects

Espinoza, C.

Publications and source records attributed to Espinoza, C..

8 recordsLinked to original sources

bioRxiv2026

GSPlot: Visualizing gene set similarity in enrichment results

SummaryInterpretation of gene set enrichment analyses is challenging when the results contain many sets. Similarities in those sets can be used for complexity management. We present GSPlot, a web-based application for visualizing enrichment results of large gene set collections. GSPlot displays gene sets in a two-dimensional space where distances reflect the similarity of their enriched content. This view brings a higher-level structure to the enrichment results and simplifies their interpretation and communication. Availability and implementationGSPlot is available at https://gsplot.cs.umb.edu/. Source code is available at https://github.com/PathwayAndDataAnalysis/gsplot.

Systems Biology↗

bioRxiv2026

A Druggable G Protein Checkpoint in Cholesterol Efflux

Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to resolve lipid overload via reverse cholesterol transport (RCT), the bodys sole pathway for lipid disposal. How RCT is restrained in disease remains unknown. Integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations associated with plaque progression and uncover CCDC88A (GIV) as a macrophage-intrinsic checkpoint on RCT. Myeloid-specific GIV deletion in mice reduces aortic plaque burden, mobilizes hepatic and adipose lipid stores and promotes fecal sterol disposal. Mechanistically, GIV sequesters the cholesterol transporter ABCA1 within endomembranes and activates Gi[bullet]{beta}{gamma} signaling to suppress cAMP/PKA-CREB-dependent efflux programs. Pharmacogenomic disruption of this checkpoint reactivates efflux programs. In human plaque-in-a-dish models targeting this pathway restored efflux where statins and {beta}-blockers failed, translating to an estimated [~]98% reduction in plaque-progression risk in outcome modeling. Thus, RCT-restoration represents a macrophage-intrinsic therapeutic paradigm for immunometabolic disease. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/705962v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@50dd10org.highwire.dtl.DTLVardef@e16d9borg.highwire.dtl.DTLVardef@1e2eaf3org.highwire.dtl.DTLVardef@af29b9_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC blurbLipid-associated macrophages drive immunometabolic disease. Katkar et al. show that disabling a GIV-dependent G-protein brake restores cholesterol efflux, reverses plaque lipid accumulation, and establishes reverse cholesterol transport as a druggable therapeutic axis. HighlightsO_LIStatins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunction C_LIO_LIGIV (CCDC88A) non-canonically modulates Gi to suppress macrophage cholesterol efflux C_LIO_LIGIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational control C_LIO_LIBlocking GIV[bullet]Gi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overload C_LIO_LISIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease C_LI

immunology↗

bioRxiv2025

Distinct Colitis-Associated Macrophages Drive NOD2-DependentBacterial Sensing and Gut Homeostasis

Single-cell studies have revealed that intestinal macrophages maintain gut homeostasis through the balanced actions of reactive (inflammatory) and tolerant (non-inflammatory) subpopulations. How such balance is impaired in inflammatory bowel diseases (IBD), including Crohns disease (CD) and ulcerative colitis (UC), remains unresolved. Here, we define colon-specific macrophage states and reveal the critical role of non-inflammatory colon-associated macrophages (niColAMs) in IBD recovery. Through trans-scale analyses--integrating computational transcriptomics, proteomics, and in vivo interventional studies--we identified GIV (CCDC88A) as a key regulator of niColAMs. GIV emerged as the top-ranked gene in niColAMs that physically and functionally interacts with NOD2, an innate immune sensor implicated in CD and UC. Myeloid-specific GIV depletion exacerbates infectious colitis, prolongs disease, and abolishes the protective effects of the NOD2 ligand, muramyl dipeptide, in colitis and sepsis models. Mechanistically, GIVs C-terminus binds the terminal leucine-rich repeat (LRR#10) of NOD2 and is required for NOD2 to dampen inflammation and clear microbes. The CD-associated 1007fs NOD2-variant, which lacks LRR#10, cannot bind GIV--providing critical insights into how this clinically relevant variant impairs microbial sensing and clearance. These findings illuminate a critical GIV-NOD2 axis essential for gut homeostasis and highlight its disruption as a driver of dysbiosis and inflammation in IBD.

immunology↗

bioRxiv2023

Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice

Idiopathic Pulmonary Fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. IPF patients have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF-associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-mesenchymal transition, and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and the Lewis Lung Carcinoma models. Models of pulmonary fibrosis, particularly bleomycin-induced fibrosis, do not recapitulate all aspects of human disease; however, to simplify nomenclature, we refer to our bleomycin-induced fibrosis model as IPF. We demonstrate that development of pulmonary fibrosis-associated lung cancer is linked to increased recruitment or reprogramming of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, pre-existing fibrosis provides a pre-metastatic niche and results in augmented tumor growth. Tumors associated with bleomycin-induced fibrosis are characterized by an epithelial-to-mesenchymal transition characterized by dramatic loss of cytokeratin expression. ImplicationsWe provide new therapeutic targets that may aid the characterization of tumors associated with lung diseases and development of treatment paradigms for lung cancer patients with pre-existing pulmonary diseases.

cancer biology↗

bioRxiv2023

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions

The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Statement of significanceThe causes underlying the onset of pancreatic cancer remain largely unknown, hampering early detection and prevention strategies. Here, we show that PanIN are abundant in healthy individuals and present at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression.

cancer biology↗

bioRxiv2022

Arginase 1 is a key driver of immune suppression in pancreatic cancer

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by expression of the enzyme Arginase 1 (Arg1), which we demonstrated is potently expressed in pancreatic tumor associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, Arg1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Thus, our data demonstrate that Arg1 is more than simply a marker of macrophage function. Rather, Arg1 is also a driver of immune suppression and represents a promising immunotherapeutic target for pancreatic cancer.

cancer biology↗

bioRxiv2021

The grape MYB24 mediates the coordination of light-induced terpene and flavonol accumulation in response to berry anthocyanin sunscreen depletion

The presence of naturally-occurring color mutants in plants has permitted the identification of many regulatory genes implicated in the synthesis of discrete metabolic compounds, mostly anthocyanins and carotenoids. Conversely, transcription factors that coordinate more than one specialized metabolic pathway seem challenging to screen from a forward genetics perspective. We explored the relationship between different branches of the phenylpropanoid and isoprenoid pathways while examining an infrequent berry skin color variegation in grapevine. Red and white berry skin sections were compared at the genetic, transcriptomic and metabolomic levels showing that, as in most cultivated white grape varieties, the uncolored skin section convened the non-functional alleles of the anthocyanin regulators MYBA1 and MYBA2, explaining the lack of pigments. In contrast, light-responsive flavonols and monoterpenes increased in anthocyanin-depleted areas. We disclosed an enrichment of the flavonol, terpene and carotenoid pathways among up-regulated genes from white-skin sections, accompanied by increased expressions of flavonol regulators and the still uncharacterized MYB24 gene. We used DAP-seq to examine the in vitro binding of affinity-purified MYB24 protein to genomic DNA and demonstrated its binding in the promoter regions of terpene (22) and carotenoid (6) genes, in addition to more than 30 photosynthesis and light-response genes, including the flavonol-regulator HY5 homologue (HYH). We confirmed the activation of TPS35 and HYH promoter:luciferase reporters in the presence of MYB24 and the grape bHLH MYC2, all of which correlate in their higher expression in white skin variegated sections. The integration of several datasets allowed to define a list of high confidence targets, suggesting MYB24 as a modulator of light responses including the synthesis of flavonoids (flavonols) and isoprenoids (terpenes, and putatively carotenoids). The correspondence between MYB24 and monoterpenes in all conditions surveyed implies that this regulatory network is broadly triggered towards berry ripening, and that the absence of anthocyanin sunscreens accelerates its activation most likely in a dose-dependent manner due to increased radiation exposure.

plant biology↗

bioRxiv2019

Fast signaling and focal connectivity of PV+ interneurons ensure efficient patternseparation by lateral inhibition in a full-scale dentate gyrus network model

Pattern separation is a fundamental brain computation that converts small differences in synaptic input patterns into large differences in action potential (AP) output patterns. Pattern separation plays a key role in the dentate gyrus, enabling the efficient storage and recall of memories in downstream hippocampal CA3 networks. Several mechanisms for pattern separation have been proposed, including expansion of coding space, sparsification of neuronal activity, and simple thresholding mechanisms. Alternatively, a winner-takes-all mechanism, in which the most excited cells inhibit all less-excited cells by lateral inhibition, might be involved. Although such a mechanism is computationally powerful, it remains unclear whether it operates in biological networks. Here, we develop a full-scale network model of the dentate gyrus, comprised of granule cells (GCs) and parvalbumin+ (PV+) inhibitory interneurons, based on experimentally determined biophysical cellular properties and synaptic connectivity rules. Our results demonstrate that a biologically realistic principal neuron-interneuron (PN-IN) network model is a highly efficient pattern separator. Mechanistic dissection in the model revealed that a winner-takes-all mechanism by lateral inhibition plays a crucial role in pattern separation. Furthermore, both fast signaling properties of PV+ interneurons and focal GC-interneuron connectivity are essential for efficient pattern separation. Thus, PV+ interneurons are not only involved in basic microcircuit functions, but also contribute to higher-order computations in neuronal networks, such as pattern separation.

neuroscience↗