Biology subjects

Verhey, T. B.

Publications and source records attributed to Verhey, T. B..

5 recordsLinked to original sources

bioRxiv2026

Microbiome-derived hydroxyphenyl propanoates enhance antitumour immunity by potentiating gasdermin D activity in tumour-associated myeloid cells

The microbiome plays a critical role in immune health and response to immune-stimulating treatments, including cancer immunotherapy. However, the molecular mechanisms by which commensal microbes influence cancer immunology remain poorly understood. Here, we report a class of microbiome-derived metabolites called hydroxyphenyl propanoates (HPP) that enhance tumour immune surveillance and response to immune checkpoint blockade (ICB) therapy in mice. HPPs function as potentiators of innate immune signalling in tumour-associated myeloid cells by promoting cleavage of the pore-forming protein gasdermin D (GSDMD), a critical effector of inflammasome function. This enhances the secretion of proinflammatory cytokines, such as IL-1 family members, while simultaneously protecting against pyroptosis. Secreted IL-1 family cytokines in turn elicit autocrine and paracrine inflammatory signaling in tumour-infiltrating leukocytes. HPP supplementation increases anticancer T cell function, improves disease control and extends overall survival (OS) in tumour-bearing mice harboring complex microbiomes or those treated with broad-spectrum antibiotics. In humans, GSDMD activation is associated with a favourable response to PD-1 blockade therapy in patients with advanced stage melanoma. Our study uncovers a molecular mechanism of regulation over host antitumour immunity that is modifiable and can be harnessed for improved cancer immunotherapy in a broad spectrum of patients.

cancer biology↗

bioRxiv2025

XenoSignal: Investigating Intra- and Inter-Species Ligand-Receptor Interactions Using AlphaFold3

Xenograft models, in which human tumors are implanted into mouse hosts, offer a unique platform to study tumor-microenvironment (TME) interactions. Ligand-receptor (LR) interactions are central to intercellular communication in this context, but most inference tools rely on single-species databases and assume conserved function across orthologues. To test whether this assumption holds given sequence and structural divergence, we developed XenoSignal, a computational framework that integrates AlphaFold3 structural predictions to assess the plausibility of intraspecies and interspecies LR interactions. The pipeline predicts whether human-mouse orthologues retain or lose their functional interaction, enabling construction of a high-confidence cross-species LR resource. XenoSignal facilitates the interpretation of tumor-TME crosstalk in xenografts and prioritizes LR pairs for experimental validation. This resource enhances our ability to dissect interspecies signaling, uncover mechanisms of immune evasion, and identify candidate therapeutic targets in translational cancer models.

bioinformatics↗

bioRxiv2025

spOT-NMF: Optimal Transport-Based Matrix Factorization for Accurate Deconvolution of Spatial Transcriptomics

Spatial transcriptomics technologies advance our understanding of complex biology by directly profiling cellular organization within tissues. However, accurate deconvolution of cell types and functional states remains challenging as most current computational methods either rely on high-quality matched single-cell reference profiles (often lacking for many tissues or disease states), struggle across spatial resolutions and under variable sequencing depths, and face scalability bottlenecks in large datasets. To address these challenges, we developed an optimal transport-based non-negative matrix factorization method (spOT-NMF) that leverages the Wasserstein distance to disentangle mixed gene expression signals in a reference-free manner. Benchmarking against well-established unsupervised deconvolution approaches demonstrates top performance of spOT-NMF in simulated and real spatial transcriptomics data spanning sub-cellular to multi-cellular resolutions, across multiple platforms, in two-species admixture scenarios such as xenografts, and in human cancer. We provide spOT-NMF as a freely available package for spatial data analysis, supporting GPU acceleration for large-scale analyses.

bioinformatics↗

bioRxiv2024

Transendothelial migration of the Lyme disease spirochete involves spirochete internalization as an intermediate step through a transcellular pathway that involves Cdc42 and Rac1

Despite its importance in pathogenesis, the hematogenous dissemination pathway of B. burgdorferi is still largely uncharacterized. To probe the molecular details of transendothelial migration more easily, we studied this process using cultured primary or telomerase-immortalized human microvascular endothelial cells in a medium that maintains both the human cells and the spirochetes. In B. burgdorferi infected monolayers we observed [~]55% of wild-type spirochetes crossing the monolayer. Microscopic characterization revealed entrance points across the cellular surface rather than at cellular junctions, supporting a transcellular route. In support of this pathway, locking the endothelial junctions using a VE-PTP inhibitor did not reduce transendothelial migration. We also used inhibitors to block the most common endocytic pathways to elucidate effectors that might be involved in B. burgdorferi uptake and/or transmigration. Directly inhibiting Cdc42 reduced spirochete transmigration by impeding internalization. However, blocking Rac1 alone dramatically reduced transmigration and resulted in a concomitant increase in spirochete accumulation in the cell. Our combined results support that B. burgdorferi internalization is an intermediate step in the transendothelial migration process which requires both Cdc42 and Rac1; Cdc42 is needed for spirochete internalization while Rac1 is required for cellular egress. These are the first two host proteins implicated in B. burgdorferi transmigration across endothelial cells. IMPORTANCELyme borreliosis is caused by Borrelia burgdorferi and related bacteria. It is the most common tick-transmitted illness in the Northern Hemisphere. The ability of this pathogen to spread to a wide variety of locations results in a diverse set of clinical manisfestations, yet little is known regarding vascular escape of the spirochete, an important pathway for dissemination. Our current work has studied the traversal of B. burgdorferi across a monolayer of microvascular endothelial cells grown in culture. We show that this occurs by passage of the spirochetes directly through these cells rather than at cellular junctions and that internalization of B. burgdorferi is an intermediate step in the transmigration process. We also identify the first two host proteins, Cdc42 and Rac1, that are used by the spirochetes to promote traversal of the cellular monolayer. Our new experimental system also provides a new avenue for further studies of this important process.

microbiology↗

bioRxiv2023

mosaicMPI: a framework for modular data integration across cohorts and -omics modalities

Advances in molecular profiling have facilitated generation of large multi-modal datasets that can potentially reveal critical axes of biological variation underlying complex diseases. Distilling biological meaning, however, requires computational strategies that can perform mosaic integration across diverse cohorts and datatypes. Here, we present mosaicMPI, a framework for discovery of low to high-resolution molecular programs representing both cell types and states, and integration within and across datasets into a network representing biological themes. Using existing datasets in glioblastoma, we demonstrate that this approach robustly integrates single cell and bulk programs across multiple platforms. Clinical and molecular annotations from cohorts are statistically propagated onto this network of programs, yielding a richly characterized landscape of biological themes. This enables deep understanding of individual tumor samples, systematic exploration of relationships between modalities, and generation of a reference map onto which new datasets can rapidly be mapped. mosaicMPI is available at https://github.com/MorrissyLab/mosaicMPI.

bioinformatics↗