Biology subjects

Haley, M. J.

Publications and source records attributed to Haley, M. J..

5 recordsLinked to original sources

bioRxiv2026

Proteomics-constrained deconvolution reveals spatial cell-type programs in tumours

Accurately resolving cell-type mixtures in spatial transcriptomics remains challenging, particularly in heterogeneous tumours where cell populations are intermixed and matched single-cell references may be unavailable or poorly aligned. Current deconvolution approaches either require high-quality scRNA-seq references, suffer from scalability limitations, or lack interpretability. We introduce PISTACHIO, a proteomics-informed spatial transcriptomics deconvolution framework based on constrained non-negative matrix factorization with a negative-binomial likelihood. Rather than using probabilistic priors, PISTACHIO incorporates spatial cell-type constraints derived from paired Imaging Mass Cytometry, enforcing biologically grounded sparsity and explicit spatial feasibility of cell-type presence. PISTACHIO improved recovery of spatial cell-type distributions compared with Cell2location and STdeconvolve across synthetic and real tumour datasets. Our approach remains robust under cell-type assignment errors, maintaining high correlation with ground-truth under moderate noise, and achieves fast runtime on standard hardware, enabling practical large-scale deployment.

bioinformatics↗

bioRxiv2026

Using atorvastatin-induced vascular weakness to model brain haemorrhage in vascularised cerebral organoids

Intracerebral haemorrhage is the most severe subtype of stroke; however, pre-clinical investigation often fails to translate to the clinic. Cerebral organoids offer an adaptable, in vitro model of human brain tissue for pre-clinical investigation of disease. We recently demonstrated that the tissue can be successfully vascularised to mimic the cerebrovasculature. Cerebrovascular weakness was induced with atorvastatin to mimic damage observed in intracerebral haemorrhage and to replicate the diseases pathological features. We used atorvastatin to disrupt functional morphology in human brain microvascular endothelial cells in 2D and 3D model systems. Whole human blood was added to initiate damage to cerebral tissues. Vascularised cerebral organoids exhibited loss of vascular integrity when treated with atorvastatin. Tissue was vulnerable to injury from human whole blood, and an innate immune response was initiated, resulting in increased cell death. Here we show that vascularised cerebral organoids demonstrate a novel model platform for investigating pathology associated with human whole blood insult in intracerebral haemorrhage.

neuroscience↗

bioRxiv2024

High-Dimensional Imaging of Vestibular Schwannoma Reveals Distinctive Immunological Networks Across Histomorphic Niches in NF2-related Schwannomatosis

NF2-related Schwannomatosis (NF2 SWN) is a rare tumour-predisposition syndrome characterised by the growth of multiple central and peripheral nervous system neoplasms. The drivers of NF2 SWN are pathogenic variants in the tumour suppressor gene NF2, encoding the protein Merlin, leading to development of bilateral vestibular schwannoma (VS) in >95% of patients. VS tumours are characterised by infiltration of myeloid cells and lymphocytes, highlighting the potential of immunotherapy for VS. However, the immunological landscape in VS and the spatial determinants within the tumour microenvironment that shape the trajectory of disease are presently unknown. In this study, to elucidate the complex immunological networks across VS, we performed imaging mass cytometry (IMC) on clinically annotated VS samples from NF2 SWN patients. We reveal the heterogeneity in neoplastic cell, myeloid cell and T cell populations that co-exist within VS, determining that the cellular composition of VS tumours is independent of NF2-SWN genetic severity. We show that distinct myeloid cell and Schwann cell populations exist within varied spatial contextures across characteristic Antoni A and B histomorphic niches. Interestingly, we show that T-cell populations associate with tumour-associated macrophages (TAMs) in Antoni A regions, seemingly limiting their ability to interact with tumorigenic Schwann cells. This spatial landscape is altered in Antoni B regions, where T-cell populations appear to interact with PD-L1+ Schwann cells. We also demonstrate that prior bevacizumab treatment (VEGF-A antagonist) preferentially reduces alternatively-activated TAMs, whilst enhancing CD44 expression, in bevacizumab-treated tumours. Together, we describe niche-dependent modes of T-cell regulation in NF2 SWN VS, indicating the potential for microenvironment-altering therapies for VS. TeaserImaging mass cytometry and spatial omic analyses illustrate spatially-distinct regions of T-cell regulation in vestibular schwannoma.

immunology↗

bioRxiv2023

Spatially resolved single-cell atlas of the lung in fatal Covid19 in an African population reveals a distinct cellular signature and an interferon gamma dominated response

Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTD) including Covid19 but there is almost no data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. We used histology and high-dimensional imaging to characterise fatal lung disease in Malawian adults with (n=9) and without (n=7) Covid19, and generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved Covid19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in the Malawi cohort, by response to interferon-gamma (IFN-{gamma}) in lung-resident alveolar macrophages, in USA, European and Asian cohorts by type I/III interferon responses, particularly in blood-derived monocytes. HIV status had minimal impact on histology or immunopathology. Our study provides data resources and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment.

immunology↗

bioRxiv2023

Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect outcome

Myeloid cells are highly prevalent in glioblastoma (GBM), existing in a spectrum of phenotypic and activation states. We currently have limited knowledge of the tumour microenvironment (TME) determinants that influence the localisation and the functions of the diverse myeloid cell populations in GBM. Here we have utilised orthogonal imaging mass cytometry with single cell and spatial transcriptomics approaches to identify and map the various myeloid populations in the human GBM tumour microenvironment (TME). Our results show that different myeloid populations have distinct and reproducible compartmentalisation patterns in the GBM TME that is driven by tissue hypoxia, regional chemokine signalling, and varied homotypic and heterotypic cellular interactions. We subsequently identified specific tumour sub-regions in GBM, based upon composition of identified myeloid cell populations, that were linked to patient survival. Our results provide new insight into the spatial organisation of myeloid cell sub populations in GBM, and how this is predictive of clinical outcome. TeaserMulti-modal mapping reveals that the spatial organisation of myeloid cells in glioblastoma impacts disease outcome.

cancer biology↗