An integrated single-cell RNA-seq map of human neuroblastoma tumors and preclinical models uncovers divergent mesenchymal-like gene expression programs

Abstract

Neuroblastoma is a common pediatric cancer, where preclinical studies have suggested chemotherapy resistance is driven by a mesenchymal-like gene expression program. However, the poor clinical outcomes imply we need a better understanding of the relationship between patient tumors and preclinical models. Here, we generated single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM). We developed an unsupervised machine learning approach to compare the gene expression programs found in preclinical models to a large cohort of human neuroblastoma tumors. The dominant adrenergic programs were well preserved in preclinical models, but contrary to previous reports do not unambiguously map to an obvious cell of origin. The mesenchymal-like program was less clearly preserved, and primarily restricted to cancer-associated fibroblasts and Schwann-like cellsin vivo. Surprisingly however, we identified a subtle, weakly expressed, mesenchymal-like program in otherwise adrenergic cancer cells in some high-risk tumors. This program appears distinct from mesenchymal cell lines but was maintained in PDX and a similar program could be chemotherapy-induced in our GEMM after only 24 hours, suggesting an uncharacterized therapy-escape mechanism. Collectively, our findings advance the understanding of neuroblastoma heterogeneity and can inform the development of new treatments.

A spatial cell atlas of neuroblastoma reveals developmental, epigenetic and spatial axis of tumor heterogeneity

“…However, other neuroblastoma singlecell studies have raised the question of whether MES cells are bona fide malignant cells. Indeed, a variety of non-malignant cells (Schwann cells, SCPs, fibroblasts, myofibroblasts) that express mesenchymal genes are present in neuroblastoma tumors, making it difficult to discern bona fide MES neuroblastoma cells from non-malignant cells expressing similar gene expression programs 81 . In our analysis, we separated MES and ADRN malignant cells and showed that both populations had the same inferred copy number variation.…”