Biology subjects

Foster, D. S.

Publications and source records attributed to Foster, D. S..

5 recordsLinked to original sources

bioRxiv2026

A Pan-Cancer Single-Cell Atlas to Evaluate Tumor Identity, Cell Line Concordance, and Dependency Mapping

Bulk RNA sequencing enables pan-cancer transcriptional analyses, but obscures cancer cell-specific programs due to admixture with nonmalignant cells, thereby limiting direct comparison between experimental models and primary tumors. Single-cell RNA sequencing (scRNA-seq) overcomes these limitations; however, the biological interpretability of public datasets is often compromised by variable data quality, inconsistent annotation, and atlas-scale aggregation strategies that prioritize data volume over biological coherence. We therefore developed a stringent integration framework that prioritizes representative malignant transcriptional states. Using Mahalanobis distance-based selection within batch-corrected latent space, we constructed a pan-cancer atlas comprising 135,424 high-quality malignant cells from 499 samples across 36 adult and pediatric cancers. Atlas-derived cancer signatures were used to determine tumor-cell line concordance and project ElasticNet models trained on DepMap CRISPR screens to infer cancer-specific gene dependencies. The scTumor Atlas establishes a scalable framework for tumor identity inference, cancer cell line benchmarking, and systematic identification of genetic vulnerabilities.

cancer biology↗

bioRxiv2025

Multidimensional Single-Cell Transcriptomic Profiling of Uterine Leiomyosarcomas Identifies Molecular Subtypes with Distinct Therapeutic Vulnerabilities

Uterine leiomyosarcoma (ULMS) is an orphan disease that frequently recurs and metastasizes, with patients undergoing multiple lines of chemotherapy due to lack of effective therapeutic targets. To address this gap, we used single-cell RNA sequencing and spatial transcriptomic analysis to comprehensively profile ULMS. We uncovered multiple states of tumor cells, including tumor cells with mesenchyme-like features, ischemic tumor cells defined by a MYC program, inflammatory tumor cells with active interferon signaling, and stem cell-like hormone receptor-positive cells. The inferred spatial correlates of these tumor cell states demonstrated unique localization patterns. By correlating these signatures to bulk RNA sequencing data, we demonstrate the relevance of these findings to clinical outcomes. Finally, using the single-cell integration and drug response prediction algorithm (scIDUC), we propose drug predictions that may target specific tumor states. Our findings suggest new avenues for further exploration of individualized and multifaceted therapeutic strategies to treat ULMS.

cancer biology↗

bioRxiv2021

Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state

Cell cycle (CC) is a fundamental biological process with robust, cyclical gene expression programs to facilitate cell division. In the immune system, a productive immune response requires the expansion of pathogen-responsive cell types, but whether CC also confers unique gene expression programs that inform the subsequent immunological response remains unclear. Here we demonstrate that single macrophages adopt different plasticity states in CC, which is a major source of heterogeneity in response to polarizing cytokines. Specifically, macrophage plasticity to interferon gamma (IFNG) is substantially reduced, while interleukin 4 (IL-4) can induce S-G2/M-biased gene expression. Additionally, IL-4 polarization shifts the CC-phase distribution of the population towards G2/M phase, providing a mechanism for reduced IFNG-induced repolarization. Finally, we show that macrophages express tissue remodeling genes in the S-G2/M-phases of CC, that can be also detected in vivo during muscle regeneration. Therefore, macrophage inflammatory and regenerative responses are gated by CC in a cyclical phase-dependent manner. HighlightsO_LISingle-cell chromatin maps reveal heterogeneous macrophage polarization states C_LIO_LICell cycle coincides with heterogeneity and alters macrophage plasticity to polarizing cytokines C_LIO_LIMacrophage polarization is a cell cycle phase-dependent immunological process C_LIO_LIS-G2/M-biased gene expression is linked to tissue remodeling and detected in proliferating macrophages during muscle regeneration C_LI

immunology↗

bioRxiv2021

Integrated spatial multi-omics reveals fibroblast fate during tissue repair

In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to define the mechanisms controlling cell fate during migration, proliferation, and differentiation following tissue injury and thereby reexamine the canonical phases of wound healing. These findings have broad implications for the study of tissue repair in complex organ systems.

bioinformatics↗

bioRxiv2020

Divergent molecular signatures of regeneration and fibrosis during wound repair

Regeneration is the "holy grail" of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward either scarring or regenerative fates. We profile scarring versus YAP inhibition-induced wound regeneration at the transcriptional (single-cell RNA-sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell surface barcoding, we integrate these data to reveal fibrotic and regenerative "molecular trajectories" of healing. We show that disrupting YAP mechanical signaling yields regenerative repair orchestrated by fibroblasts with activated Trps1 and Wnt signaling. Our findings serve as a multimodal map of wound regeneration and could have therapeutic implications for pathologic fibroses.

cell biology↗