Comparative Single-Cell Transcriptomics of Human Neuroblastoma and Preclinical Models Reveals Conservation of an Adrenergic Cell State.

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 (NB), remains to be validated. Here, we characterized the transcriptional landscape of TH-MYCN tumors by single-cell RNA sequencing (scRNA-seq) 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 NB patients and TH-MYCN mice demonstrated similarities in adrenergic tumor cell composition. Ex vivo tumoroid cultures displayed histological resemblance and shared transcriptional profiles with the originating TH-MYCN tumors and human NB. Importantly, subpopulations within tumoroids exhibited gene expression associated with poor NB patient survival. 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 NB. Together, this study not only deepens our understanding of a widely used transgenic mouse NB model but also introduces an ex vivo model that maintains critical adrenergic cell state identity, thereby enhancing its translational potential for NB research.