Single-cell RNA-seq reveals the transcriptional program underlying tumor progression and metastasis in neuroblastoma

Abstract

Neuroblastoma (NB) is one of the most common childhood malignancies. Sixty percent of patients present with widely disseminated clinical signs at diagnosis and exhibit poor outcomes. However, the molecular mechanisms triggering NB metastasis remain largely uncharacterized. In this study, we generated a transcriptomic atlas of 15 447 NB cells from eight NB samples, including paired samples of primary tumors and bone marrow metastases. We used time-resolved analysis to chart the evolutionary trajectory of NB cells from the primary tumor to the metastases in the same patient and identified a common ‘starter’ subpopulation that initiates tumor development and metastasis. The ‘starter’ population exhibited high expression levels of multiple cell cycle-related genes, indicating the important role of cell cycle upregulation in NB tumor progression. In addition, our evolutionary trajectory analysis demonstrated the involvement of partial epithelial-to-mesenchymal transition (p-EMT) along the metastatic route from the primary site to the bone marrow. Our study provides insights into the program driving NB metastasis and presents a signature of metastasis-initiating cells as an independent prognostic indicator and potential therapeutic target to inhibit the initiation of NB metastasis.

Keywords

single-cell RNA sequencing / metastasis / neuroblastoma / epithelial-to-mesenchymal transition

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81825017, 81773034 to Zhe Liu, 8217113342, 81872350 to Zhenyi Ma), the Ministry of Science and Technology of China (No. 2018YFC1313002 to Zhe Liu), the Tianjin Municipal Science and Technology Commission (No. 20JCZDJC00110 to Zhe Liu), the Interdisciplinary Research Project of Hangzhou Normal University (No. 2024JCXK03 to Zhe Liu), and the Haihe Laboratory of Cell Ecosystem Innovation Fund (No. HH22KYZX0025 to Zhe Liu).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1081-7 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Zhe Nian, Dan Wang, Hao Wang, Wenxu Liu, Zhenyi Ma, Jie Yan, Yanna Cao, Jie Li, Qiang Zhao, and Zhe Liu declare that they have no conflict of interest.

This study was approved by the Institutional Ethics Committee of Tianjin Medical University Cancer Institute and Hospital, Tianjin, China (Approve number: E20210664). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

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