In a recent study published in Developmental Cell, researchers at Karolinska Institutet created a comprehensive map of neuroblastoma at the cellular level by integrating single-cell transcriptomics, single-cell multi-omics, and spatial transcriptomics.
High-risk neuroblastoma kills roughly half of affected children because the tumor can switch cell identity and evade therapy. By combining single-cell multi-omics with spatial transcriptomics, researchers at Karolinska Institutet have constructed a cell-by-cell roadmap of these state transitions.
The researchers revealed an enhancer‑primed epigenetic landscape that gives neuroblastoma cells the latent capacity to shift between developmental programs. They also discovered a hidden intermediate state that orchestrates these transitions. By finding the enhancer-driven gene networks that power these shifts, they identified key transcription-factor 'switches' whose inhibition locks the cancer into a less aggressive state.
Effectiveness of existing treatments
"High-risk neuroblastoma remains deadly because its tumor cells can change their transcriptomic identity and sidestep therapy. Our study pinpoints the intermediate 'bridge' cell state that mediates this plasticity and maps the gene regulatory networks that control it, giving researchers clear molecular targets for new drugs and combination therapies", explains Yizhou Hu , co-author and principal researcher at the Department of Laboratory Medicine at Karolinska Institutet.
The findings also highlight the role of the tumor microenvironment in sustaining these aggressive cell states. Tumor-associated macrophages and cancer-associated fibroblasts were found to cluster around bridge and neural crest-like tumor cells, supporting their behavior.
"Targeting the newly identified transcription factor switches or the supportive microenvironment could lock the tumor into a less dangerous state and enhance the effectiveness of existing treatments. A diagnostic test measuring the proportion of bridge/neural crest state cells could help clinicians determine the appropriate level of therapy for each patient", says Patrik Ernfors , co-author and professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.
The research team now plans to explore ways to disrupt the microenvironmental niche that sustains high-risk cell states in neuroblastoma. They also aim to develop a practical diagnostic panel based on their single-cell signatures and test new therapeutic approaches that target the transcription factor circuits driving tumor cell state changes.
Collaboration and funding
Conducted with Professor Jian Wang (Children's Hospital of Soochow University, China), and in close collaboration with Senior Lecturer Susanne Schlisio (Karolinska Institutet, Sweden), Professor Arthur Tischler (Tufts Medical Center, USA), and Professor Ronald R. de Krijger (Princess Máxima Center for Pediatric Oncology, Netherlands).
Funders: Swedish Medical Research Council, Cancerfonden, Knut and Alice Wallenberg Foundation, SSMF, Åke Wiberg Research Grant, Karolinska Institute Research Grant.
Publication
Xu Y, Lou D, Chen P, Li G, Usoskin D, Pan J, Li F, Huang S, Hess C, Tang R, Hu X, Yu J, Arceo M, de Krijger RR, Tischler AS, Schlisio S, Ernfors P, Hu Y, Wang J
Dev Cell 2025 May;():
