Biology subjects

Joyce, J. A.

Publications and source records attributed to Joyce, J. A..

6 recordsLinked to original sources

bioRxiv2026

SuperCell2.0 enables semi-supervised construction of multimodal metacell atlases

Multimodal single-cell atlases comprising hundreds of thousands of cells provide unique resources for exploring complex biological tissues and generating testable hypotheses. To streamline the analysis of such large datasets, we introduce SuperCell2.0, a robust workflow to build (semi-)supervised multimodal metacells. We demonstrate that multimodal metacells outperform metacells built with a single modality, improve inter-modality consistency, and facilitate integration of multiomic single-cell datasets. SuperCell2.0 can further leverage full or partial cell type annotations to improve metacell quality. This workflow enables us to construct multimodal metacell atlases from blood and tumor samples and identifies interferon-primed monocytes and macrophages in the circulation and in the tumor microenvironment. Markers derived from the metacell analysis enable us to sort and phenotypically characterize this population in healthy donors. Overall, our work demonstrates how SuperCell2.0 facilitates the analysis of large multimodal single-cell atlases.

bioinformatics↗

bioRxiv2025

Multi-cellular phenotypic dynamics during the progression of breast tumors

In cancer, improving diagnostics and therapeutic interventions can benefit from understanding the cellular and phenotypic heterogeneity of the tumor microenvironment (TME). In recent years, the TME has been profiled at an unprecedented level of detail by performing single-cell RNA sequencing (scRNAseq) on patient samples. However, from patient samples, studying the temporal dynamics of the TME using patient samples has been challenging. Interrogating the temporal dynamics of the TME is critical to understand how inter-tumor heterogeneity is organized into a temporally ordered sequence of causes and consequences in cellular events. Here we survey the temporal dynamics of the TME by performing longitudinal scRNAseq on mouse breast tumors at different progression time points of tumor progression. We reveal multi-cellular phenotypic dynamics that follow one out of three possible temporal patterns: stable colonization, wave-like, or progressive increase. In particular, IFN-responsive cancer cells, GzmB + cytotoxic T cells, as well as C1q macrophages, progressively increase in parallel with tumors progression. These findings establish the single-cell types and phenotypes in a progressing breast tumor, and determine when these cellular players enter and leave the TME.

cancer biology↗

bioRxiv2023

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

cancer biology↗

bioRxiv2021

Exploration and analysis of molecularly annotated, 3D models of breast cancer at single-cell resolution using virtual reality

A set of increasingly powerful approaches are enabling spatially resolved measurements of growing numbers of molecular features in biological samples. While important insights can be derived from the two-dimensional data that many of these technologies generate, it is clear that extending these approaches into the third and fourth dimensions will magnify their impact. Realizing biological insights from datasets where thousands to millions of cells are annotated with tens to hundreds of parameters in space will require the development of new computational and visualization strategies. Here, we describe Theia, a virtual reality-based platform, which enables exploration and analysis of either volumetric or segmented, molecularly-annotated, three-dimensional datasets, with the option to extend the analysis to time-series data. We also describe our pipeline for generating annotated 3D models of breast cancer and supply several datasets to enable users to explore the utility of Theia for understanding cancer biology in three dimensions.

cancer biology↗

bioRxiv2021

Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis

Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant non-malignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. We used an inhibitor of colony stimulating factor 1 receptor (CSF1R) to target TAMs at distinct stages of the metastatic cascade in preclinical breast-to-brain metastasis models and found that CSF1R inhibition leads to anti-tumor responses in prevention and intervention trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuro-inflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, combined blockade of CSF1R and STAT5 signaling led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.

cancer biology↗

bioRxiv2017

A Carbon Nanotube Optical Reporter Maps Endolysosomal Lipid Flux

Lipid accumulation within the lumen of endolysosomal vesicles is observed in various pathologies including atherosclerosis, liver disease, neurological disorders, lysosomal storage disorders, and cancer. Current methods cannot measure lipid flux specifically within the lysosomal lumen of live cells. We developed an optical reporter, composed of a photoluminescent carbon nanotube of a single chirality, which responds to lipid accumulation via modulation of the nanotubes optical bandgap. The engineered nanomaterial, composed of short-single stranded DNA and a single nanotube chirality, localizes exclusively to the lumen of endolysosomal organelles without adversely affecting cell viability or proliferation, or organelle morphology, integrity, or function. The emission wavelength of the reporter can be spatially resolved from within the endolysosomal lumen to generate quantitative maps of lipid content in live cells. Endolysosomal lipid accumulation in cell lines, an example of drug-induced phospholipidosis (DIPL), was observed for multiple drugs in macrophages, and measurements of patient-derived Niemann-Pick type C fibroblasts identified lipid accumulation and phenotypic reversal of this lysosomal storage disease. Single-cell measurements using the reporter discerned sub-cellular differences in equilibrium lipid content, illuminating significant intracellular heterogeneity among endolysosomal organelles of differentiating bone marrow-derived monocytes. Single-cell kinetics of lipoprotein-derived cholesterol accumulation within macrophages revealed rates that differed among cells by an order of magnitude. This carbon nanotube optical reporter of endolysosomal lipid content in live cells confers new capabilities for drug development processes and the investigation of lipid-linked diseases.

bioengineering↗