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PHILADELPHIA, April 14, 2025 ~ A team of researchers at Children's Hospital of Philadelphia (CHOP) has made a significant breakthrough in the understanding of neuroblastoma, a common and potentially deadly childhood cancer. Led by senior study author Kai Tan, PhD, the team developed a longitudinal atlas of neuroblastoma to gain deeper insights into the molecular mechanisms underlying treatment resistance.

Published in the journal Nature Genetics, the study offers valuable new insights that could potentially lead to personalized medicine approaches in neuroblastoma treatment. Despite significant advances in standard care, the 5-year survival rate for high-risk neuroblastoma remains less than 50%. One of the major challenges in treating this cancer is its heterogeneity, with different cells within the same tumor exhibiting varying characteristics.

The lack of understanding about how these cells interact and change during treatment has been a major barrier in developing effective therapies. In this study, researchers created a cell atlas that provided an in-depth look at how different cell types, such as malignant cells and immune cells, interact and change within their natural environment.

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"Our atlas provides a crucial foundation for developing novel treatments by mapping the complex interactions between malignant cells and surrounding cells that support tumor growth," said Dr. Tan. "As researchers, we look to use these insights to tailor therapies to target unique characteristics of a patient's tumor. Overall, we are optimistic about the doors our research and techniques are opening."

To create this atlas, CHOP researchers used advanced single-cell sequencing and spatial omics techniques to analyze tumor samples from 22 pediatric patients with high-risk neuroblastoma before and after chemotherapy. This multidimensional dataset is now available on the National Cancer Institute (NCI) Human Tumor Atlas Network (HTAN) data portal.

The team uncovered diverse characteristics of both tumor and non-tumor cells, as well as major changes in these characteristics following chemotherapy. They found that patients had worse outcomes when cancer cells were multiplying more actively and became more metabolically active. On the other hand, tumors that developed more mature, neuron-like features resulted in better outcomes for patients.

Additionally, the researchers found that an increase in a type of mesenchymal-like tumor cells was linked to poorer responses to chemotherapy. They also discovered that certain immune cells, such as macrophages, became more active in ways that promoted tumor growth by enabling blood vessel growth while suppressing the immune response.

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One of the most significant findings of the study was a specific communication pathway between macrophages and cancer cells (HB-EGF/ERBB4) that triggered signals promoting tumor growth. This highlights the importance of identifying new factors within the tumor microenvironment that influence treatment response. The team is now conducting further studies using preclinical models to test this pathway and potentially develop novel therapeutic strategies.

"This study would not have been possible without the monumental team efforts of biologists, clinicians, and computational scientists," said lead author Wenbao Yu, PhD. "With their collaboration, we were able to gain new insights into the complex ecosystem of neuroblastoma."

The research was supported by a grant from the National Cancer Institute (NCI) Human Tumor Atlas Network (#U2C CA233285), as well as grants from the National Institutes of Health (NIH) (U54 HL165442), American Cancer Society Institutional Research Grant (IRG-22-150-41-IRG), and NIH (T32 CA009140).

This groundbreaking study, titled "Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring," was published online on April 14th, 2025 in Nature Genetics. The DOI for this article is 10.1038/s41588-025-02158-6.

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