Biology subjects

Morrissy, A. S.

Publications and source records attributed to Morrissy, A. S..

3 recordsLinked to original sources

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↗

bioRxiv2022

In vivo functional genomics identifies essentiality of potassium homeostasis in medulloblastoma

The identification of cancer maintenance genes--driver genes essential to tumor survival--is fundamental for developing effective cancer therapy. Transposon-based insertional mutagenesis screens can identify cancer driver genes broadly but not discriminate maintenance from progression or initiation drivers, which contribute to cancer phenotypes and tumorigenesis, respectively. We engineered a nested, double-jumping transposon system to first dysregulate gene expression during tumorigenesis and then restore gene expression following tumor induction, allowing for genome-wide screening of maintenance essentiality in vivo. In a mouse model of medulloblastoma, the most common pediatric malignancy, insertion and remobilization of this nested transposon uncovers potassium channel genes as recurrent maintenance drivers. In human medulloblastoma, KCNB2 is the most overexpressed potassium channel across Group 3, Group 4, and SHH subgroups, and Kcnb2 knockout in mice diminishes the replicative potential of medulloblastoma-propagating cells to mitigate tumor growth. Kcnb2 governs potassium homeostasis to regulate plasma membrane tension-gated EGFR signaling, which drives proliferative expansion of medulloblastoma-propagating cells. Thus, our novel transposon system reveals potassium homeostasis as essential to tumor maintenance through biomechanical modulation of membrane signaling.

cancer biology↗