Trajectory analysis reveals an uncommitted neuroblastic state in MYCN-driven neuroblastoma development.

BACKGROUND: Understanding the factors that determine the spontaneous regression of pre-cancerous lesions is critical to advancing cancer prevention. Neuroblastoma, a pediatric cancer, undergoes spontaneous regression more frequently than other types of cancer. METHODS: Here, we analyzed the transcriptomic features of spontaneous regression in pre-cancerous neuroblasts using Th-MYCN mice, an animal model that closely resembles human neuroblastoma. Single-cell transcriptomic analysis of ganglion tissues from Th-MYCN mice was conducted to elucidate the cellular and molecular underpinnings. RESULTS: Trajectory analysis of pre-cancerous neuroblasts revealed a distinct subtype we designated as "uncommitted" cells, characterized by the expression of neuronal genes, indicative of a semi-differentiated state. Samples with predicted failed tumorigenesis had a greater proportion of these uncommitted cells, hinting at their association with spontaneous regression. In clinical specimens, heightened uncommitted gene expression corresponded with favorable neuroblastomas and an improved prognosis. CONCLUSION: Collectively, the identification of this novel neuroblastoma-related cell subtype and its transcriptomic signature not only enhances our understanding of spontaneous regression mechanisms but also holds potential for therapeutic advancements in treating neuroblastomas.