Journal Article Comparative Study Ppublish 2 citations
PubMed: 39808065 DOI: 10.1158/0008-5472.CAN-24-1507
Comparative Single-Cell Transcriptomics of Human Neuroblastoma and Preclinical Models Reveals Conservation of an Adrenergic Cell State.
Cancer Res 85(6):1015-1034
Authors: Bethel Tesfai Embaie, Hirak Sarkar, Adele M Alchahin, Jörg Otte, Thale Kristin Olsen, Conny Tümmler, Polina Kameneva, Artem V Artemov, Natalia Akkuratova, Igor Adameyko, Jan-Bernd Stukenborg, Malin Wickström, Per Kogner, John Inge Johnsen, Shenglin Mei, Peter V Kharchenko, Ninib Baryawno
Affiliations
- Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
- Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts.
- Ludwig Princeton Branch, Department of Computer Science, Princeton University, Princeton, New Jersey.
- Ludwig Princeton Branch, Department of Molecular Biology, Princeton University, Princeton, New Jersey.
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
- St.Anna Children's Cancer Research Institute, Vienna, Austria.
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
- Division of Neuroimmunology, Department Center for Brain Research, Medical University of Vienna, Wien, Austria.
- San Deigo Institute of Science, Altos Labs, San Diego, California.
Abstract
Transgenic mice and organoid models, such as three-dimensional tumoroid cultures, have emerged as powerful tools for investigating cancer development and targeted therapies. Yet, the extent to which these preclinical models recapitulate the cellular identity of heterogeneous malignancies, like neuroblastoma, remains to be validated. In this study, we characterized the transcriptional landscape of TH-MYCN tumors by single-cell RNA sequencing and developed ex vivo tumoroids. Integrated analysis with murine fetal adrenal samples confirmed that both TH-MYCN tumors and tumoroids closely mirror the cellular profiles of normal embryonic sympathoblasts and chromaffin cells. Comprehensive comparison between tumors from patients with neuroblastoma and TH-MYCN mice demonstrated similarities in adrenergic tumor cell composition. Ex vivo tumoroid cultures displayed histologic resemblance and shared transcriptional profiles with the originating TH-MYCN tumors and human neuroblastoma tumors. Importantly, subpopulations within tumoroids exhibited gene expression associated with poor survival of patients with neuroblastoma. Notably, recurrent observations of a low-proliferative chromaffin phenotype connected to the highly proliferative sympathetic phenotype suggested that pushing sympathoblasts into a chromaffin-like state may offer an interesting therapeutic strategy for neuroblastoma. Together, this study not only deepens our understanding of a widely used transgenic mouse neuroblastoma model but also introduces an ex vivo model that maintains critical adrenergic cell state identity, thereby enhancing its translational potential for neuroblastoma research. Significance: Transgenic mouse models and ex vivo tumoroids, characterized through single-cell RNA sequencing, faithfully recapitulate neuroblastoma cellular identity, offering a useful platform for investigating potential therapeutic strategies.
MeSH
Cells, Genes, Adrenergic Agents, Neoplasms, Phenotype, Therapeutics, Neuroblastoma