Biology subjects

Fong, A.

Publications and source records attributed to Fong, A..

7 recordsLinked to original sources

bioRxiv2026

Developmental origins of thymic B-cell lymphomas

The thymus provides a specialized niche for lymphocyte differentiation, yet the developmental trajectories of its rare B-cell population and their relationship to thymic B-cell lymphomagenesis remain poorly understood. Here, we integrate single-cell multiomics and spatial profiling across human tissues to delineate a B-cell differentiation program selectively represented in the human thymus. This program links CCL17 and germinal center-like B-cell states along a trajectory distinct from canonical germinal center differentiation and can be recapitulated in vitro by signals operating in the thymic medulla. Extending this framework across human B-cell lymphomas, we identify an inherent malignant cell state in PMBCL that shares transcriptional and epigenetic features with CCL17 thymic B cells. This malignant state associates with early clonal positions in reconstructed B-cell receptor phylogenies and persists within tumor microenvironments distinct from the thymic niche. Together, these findings support a model in which thymus-specific B-cell differentiation programs are redeployed during thymic B-cell lymphomagenesis.

cancer biology↗

bioRxiv2026

Single-cell spatial multi-omic characterization of the tumour microenvironment in transformed follicular lymphoma

Histological examination of follicular lymphoma (FL) biopsies remains the cornerstone for diagnostic grading of FL. Single-cell sequencing approaches, while transcriptomically rich, require tissue dissociation and lose the native spatial context that underpins FL transformation to diffuse large B-cell lymphoma (DLBCL). To investigate the spatial interplay between malignant B-cells and the tumour microenvironment (TME) across disease states, we performed subcellular single-cell spatial transcriptomics and spatial proteomics on 12 paired pre/post-transformation samples and 10 non-transforming FL controls, integrated with matched single-cell whole genome sequencing (scWGS). Our analysis reveals that transformation is accompanied by a shift toward B-cell-predominant stromal and immunosuppressive cellular neighbourhoods, where the magnitude of expansion correlates with time to transformation. Prior to transformation, immunomodulatory Galectin-9 interactions move from the intra-follicular core to the extra-follicular space. Integration with scWGS demonstrates that high copy-number instability in malignant B-cells is associated with reduced supportive T-cell niches and intensified immunoregulatory crosstalk at the transformed state. Collectively, our multi-omic analysis characterizes TME remodeling during FL transformation, contributing to a refined disease evolution model.

bioinformatics↗

bioRxiv2025

Aggressive Neuroblastomas Start Growing after Infancy

In neuroblastoma, population screening during infancy failed to lower mortality because it primarily detected biologically indolent tumors rather than aggressive, life-threatening disease. The failure may reflect limited screening sensitivity, or disease onset after infancy among aggressive tumors. Here, we used an epigenetic mitotic clock based on fluctuating CpG DNA methylation to estimate patient-specific tumor mitotic ages and calendar ages in a cohort of unscreened children diagnosed with neuroblastoma. Aggressive cancers (stage 4) primarily started growing after the first year of life, making them undetectable by screening during infancy. In contrast, biologically more indolent tumors (stages 1, 2, 3 and 4S) often started growing in utero or during the first year of life, and affected children had better survival outcomes. Due to a short preclinical detectable phase of aggressive neuroblastomas, reducing mortality through screening is impractical as it would require frequent screening among older children. Patient-specific tumor-age estimation may help refine screening windows and improve early-detection strategies in other cancers where screening has so far failed to yield substantial mortality reductions.

cancer biology↗

bioRxiv2025

Microbiota promote enhanced CD39 expression in γδ intraepithelial lymphocytes through the activation of TCR and IL-15 signaling

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative {gamma}{delta} IEL ({gamma}{delta}HYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory {gamma}{delta} T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naive-like CD39neg {gamma}{delta} IEL to a more mature, tissue-adapted CD39hi IEL population. We found that TCR{gamma}{delta} activation drives CD122-mediated CD39 upregulation on {gamma}{delta}HYP IELs and increased mucosal IL-15 further amplifies CD39 expression in these cells. Further investigation revealed that CD39 induction requires sustained exposure to the {gamma}{delta}HYP-associated microbiota. Moreover, CD39hi {gamma}{delta} IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in {gamma}{delta}HYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on {gamma}{delta}HYP IELs, leading to the expansion of {gamma}{delta} IELs with regulatory potential.

immunology↗

bioRxiv2024

YibN, a bona fide interactor of YidC with implications in membrane protein insertion and membrane lipid production

YidC, a prominent member of the Oxa1 superfamily, is essential for the biogenesis of the bacterial inner membrane, significantly influencing its protein composition and lipid organization. It interacts with the Sec translocon, aiding the proper folding of multi-pass membrane proteins. It also functions independently, serving as an insertase and lipid scramblase, augmenting the insertion of smaller membrane proteins while contributing to the organization of the bilayer. Despite the wealth of structural and biochemical data available, how YidC operates remains unclear. To investigate this, we employed proximity-dependent biotin labeling (BioID), leading to the identification of YibN as a crucial component within the YidC protein environment. We then demonstrated the association between YidC and YibN by affinity purification-mass spectrometry assays conducted on native membranes, with further confirmation using on-gel binding assays with purified proteins. Co-expression studies and in vitro assays indicated that YibN enhances the production and membrane insertion of YidC substrates, such as M13 and Pf3 phage coat proteins, ATP synthase subunit c, and various small membrane proteins like SecG. Additionally, the overproduction of YibN was found to stimulate membrane lipid production and promote inner membrane proliferation, perhaps by interfering with YidC lipid scramblase activity. Consequently, YibN emerges as a significant physical and functional interactor of YidC, influencing membrane protein insertion and lipid organization.

biochemistry↗

bioRxiv2023

Dysregulation of γδ intraepithelial lymphocytes precedes Crohn's disease-like ileitis

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IELs) provide immunosurveillance of the intestinal barrier. Interestingly, {gamma}{delta} IEL number is reduced in patients with active Crohns disease (CD). Here, we report an underappreciated role for {gamma}{delta} IELs in maintaining mucosal tolerance during the onset and progression of CD-like ileitis using the TNF{Delta}ARE/+ mouse model. Decreased epithelial HNF4G/BTNL expression is followed by a loss of ileal {gamma}{delta} IELs and impaired barrier surveillance prior to the histological onset of disease. A reduction of immunoregulatory CD39+ {gamma}{delta} IELs coincides with the influx of immature, peripheral CD39- {gamma}{delta} T cells into the epithelium leading to an expansion of induced IELs, while an earlier depletion of {gamma}{delta} IELs correlates with accelerated onset of ileal inflammation. Our findings identify multiple layers of {gamma}{delta} IEL dysregulation prior to ileitis development indicating that the loss of tissue-resident immunoregulatory {gamma}{delta} IELs may contribute to the initiation of ileal CD.

immunology↗

bioRxiv2021

Proteomic portraits reveal evolutionarily conserved and divergent responses to spinal cord injury

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of CSF and serum samples from 111 acute SCI patients and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at six months with an AUC of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response, and establish the CSF abundance of glial fibrillary acidic protein (GFAP) as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts.

neuroscience↗