Biology subjects

Weng, A. P.

Publications and source records attributed to Weng, A. P..

5 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↗

bioRxiv2025

Multidimensional characterization of cellular ecosystems in Hodgkin lymphoma

The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.

cancer biology↗

bioRxiv2023

The spatially resolved tumor microenvironment predicts treatment outcome in relapsed/refractory Hodgkin lymphoma

PURPOSEAbout a third of relapsed or refractory classic Hodgkin lymphoma (r/r CHL) patients succumb to their disease after high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL. METHODSWe performed imaging mass cytometry (IMC) on 169 paired primary diagnostic and relapse biopsies using a marker panel specific for CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes. RESULTSHighly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early relapse/refractory CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single cell RNA sequencing data identified unique architecture defined by CXCR5+ HRS cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay ( RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk vs low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay. CONCLUSIONSWe identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.

cancer biology↗

bioRxiv2022

SpatialSort: A Bayesian Model for Clustering and CellPopulation Annotation of Spatial Proteomics Data

Emerging spatial proteomics technologies have created new opportunities to move beyond quantifying the composition of cell types in tissue and begin probing spatial structure. However, current methods for analysing such data are designed for non-spatial data and ignore spatial information. We present SpatialSort, a spatially aware Bayesian clustering approach that allows for the incorporation of prior biological knowledge. SpatialSort clusters cells by accounting for affinities of cells of different types to neighbours in space. Additionally, by incorporating prior information about cell types, SpatialSort outperforms current methods and can perform automated annotation of clusters.

bioinformatics↗

bioRxiv2019

Probabilistic cell type assignment of single-cell transcriptomic data reveals spatiotemporal microenvironment dynamics in human cancers

Single-cell RNA sequencing (scRNA-seq) has transformed biomedical research, enabling decomposition of complex tissues into disaggregated, functionally distinct cell types. For many applications, investigators wish to identify cell types with known marker genes. Typically, such cell type assignments are performed through unsupervised clustering followed by manual annotation based on these marker genes, or via \"mapping\" procedures to existing data. However, the manual interpretation required in the former case scales poorly to large datasets, which are also often prone to batch effects, while existing data for purified cell types must be available for the latter. Furthermore, unsupervised clustering can be error-prone, leading to under- and over- clustering of the cell types of interest. To overcome these issues we present CellAssign, a probabilistic model that leverages prior knowledge of cell type marker genes to annotate scRNA-seq data into pre-defined and de novo cell types. CellAssign automates the process of assigning cells in a highly scalable manner across large datasets while simultaneously controlling for batch and patient effects. We demonstrate the analytical advantages of CellAssign through extensive simulations and exemplify real-world utility to profile the spatial dynamics of high-grade serous ovarian cancer and the temporal dynamics of follicular lymphoma. Our analysis reveals subclonal malignant phenotypes and points towards an evolutionary interplay between immune and cancer cell populations with cancer cells escaping immune recognition.

bioinformatics↗