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bioRxiv · 10.64898/2026.09.08.750106

ALK variants Differentially Modulate Neuroblastoma Tumor Behavior and Transcriptome in a Cellular Context-Dependent Manner

El Natour, M.·Vivancos Stalin, L.·Gobet, N.·Praz, V.·Balmas Bourloud, K.·Jauquier, N.·Janoueix-Lerosey, I.·Riggi, N.·Renella, R.·Muhlethaler-Mottet, A.
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Abstract

High-risk neuroblastoma remains a major clinical challenge despite intensive multimodal treatment. Alterations in the anaplastic lymphoma kinase (ALK) gene are frequent in NB and correlate with poor outcome. ALK-F1174L and ALK-R1275Q are the most prevalent activating mutations, but their specific effects on tumor behavior remain unclear. Here, we compared the impacts of ALK-wild-type (wt), ALK-F1174L and ALK-R1275Q in several NB xenograft models. In the SK-N-Be2c model, ALK-F1174L mediated numerous transcriptomic alterations without affecting tumor behavior. In GIMEN cells, only ALK-F1174L and ALK-R1275Q conferred tumorigenicity with distinct growth kinetics and transcriptional programs. In the mesenchymal SH-EP model, ALK variants induced distinct phenotypes, with ALK-wt and ALK-F1174L promoting partial transition toward neuroblastic identity. All ALK variants induced lung metastases, but with allele-specific dissemination patterns. Transcriptomic profiling of SH-EP tumors and corresponding metastases revealed partly opposing pathway regulation between ALK-F1174L and ALK-R1275Q. Overall, ALK variants differentially modulate NB behavior in a context-dependent manner.

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El Natour, M., Vivancos Stalin, L., Gobet, N., Praz, V., Balmas Bourloud, K., Jauquier, N., Janoueix-Lerosey, I., Riggi, N., Renella, R., Muhlethaler-Mottet, A.. 2026-09-10. ALK variants Differentially Modulate Neuroblastoma Tumor Behavior and Transcriptome in a Cellular Context-Dependent Manner. https://doi.org/10.64898/2026.09.08.750106

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