All Publications

  • Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence. bioRxiv : the preprint server for biology Piyadasa, H., Oberlton, B., Ribi, M., Ranek, J. S., Averbukh, I., Leow, K., Amouzgar, M., Liu, C. C., Greenwald, N. F., McCaffrey, E. F., Kumar, R., Ferrian, S., Tsai, A. G., Filiz, F., Fullaway, C. C., Bosse, M., Varra, S. R., Kong, A., Sowers, C., Gephart, M. H., Nuñez-Perez, P., Yang, E., Travers, M., Schachter, M. J., Liang, S., Santi, M. R., Bucktrout, S., Gherardini, P. F., Cole, K., Barish, M. E., Brown, C. E., Oldridge, D. A., Drake, R. R., Phillips, J. J., Okada, H., Prins, R., Bendall, S. C., Angelo, M. 2025

    Abstract

    Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) evolution, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma (PXA), while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Longitudinal samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T-cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study opens new avenues for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.

    View details for DOI 10.1101/2025.03.12.642624

    View details for PubMedID 40161803

    View details for PubMedCentralID PMC11952471

  • Robust phenotyping of highly multiplexed tissue imaging data using pixel-level clustering. Nature communications Liu, C. C., Greenwald, N. F., Kong, A., McCaffrey, E. F., Leow, K. X., Mrdjen, D., Cannon, B. J., Rumberger, J. L., Varra, S. R., Angelo, M. 2023; 14 (1): 4618

    Abstract

    While technologies for multiplexed imaging have provided an unprecedented understanding of tissue composition in health and disease, interpreting this data remains a significant computational challenge. To understand the spatial organization of tissue and how it relates to disease processes, imaging studies typically focus on cell-level phenotypes. However, images can capture biologically important objects that are outside of cells, such as the extracellular matrix. Here, we describe a pipeline, Pixie, that achieves robust and quantitative annotation of pixel-level features using unsupervised clustering and show its application across a variety of biological contexts and multiplexed imaging platforms. Furthermore, current cell phenotyping strategies that rely on unsupervised clustering can be labor intensive and require large amounts of manual cluster adjustments. We demonstrate how pixel clusters that lie within cells can be used to improve cell annotations. We comprehensively evaluate pre-processing steps and parameter choices to optimize clustering performance and quantify the reproducibility of our method. Importantly, Pixie is open source and easily customizable through a user-friendly interface.

    View details for DOI 10.1038/s41467-023-40068-5

    View details for PubMedID 37528072

    View details for PubMedCentralID 6086938

  • Whole-cell segmentation of tissue images with human-level performance using large-scale data annotation and deep learning. Nature biotechnology Greenwald, N. F., Miller, G., Moen, E., Kong, A., Kagel, A., Dougherty, T., Fullaway, C. C., McIntosh, B. J., Leow, K. X., Schwartz, M. S., Pavelchek, C., Cui, S., Camplisson, I., Bar-Tal, O., Singh, J., Fong, M., Chaudhry, G., Abraham, Z., Moseley, J., Warshawsky, S., Soon, E., Greenbaum, S., Risom, T., Hollmann, T., Bendall, S. C., Keren, L., Graf, W., Angelo, M., Van Valen, D. 2021

    Abstract

    A principal challenge in the analysis of tissue imaging data is cell segmentation-the task of identifying the precise boundary of every cell in an image. To address this problem we constructed TissueNet, a dataset for training segmentation models that contains more than 1million manually labeled cells, an order of magnitude more than all previously published segmentation training datasets. We used TissueNet to train Mesmer, a deep-learning-enabled segmentation algorithm. We demonstrated that Mesmer is more accurate than previous methods, generalizes to the full diversity of tissue types and imaging platforms in TissueNet, and achieves human-level performance. Mesmer enabled the automated extraction of key cellular features, such as subcellular localization of protein signal, which was challenging with previous approaches. We then adapted Mesmer to harness cell lineage information in highly multiplexed datasets and used this enhanced version to quantify cell morphology changes during human gestation. All code, data and models are released as a community resource.

    View details for DOI 10.1038/s41587-021-01094-0

    View details for PubMedID 34795433