The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis in immunocompromised mice. Moreover, TWIST1 knock-out tumors displays a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings confirm TWIST1 as promising therapeutic target in NB. This dataset comprise images (.ndpi files) of anti-F4/80 IHC staining used for the quantification of macrophages in subcutaneous and orthotopic neuroblastoma xenografts derived from SK-N-Be2c cells expressing TWIST1 or knocked out for TWIST1 through CRISR/Cas9.

This work was supported by grants from Kinderkrebsforschung Schweiz, the Novartis Foundation for Medical-Biological Research, the Hubert Gouin Association, and the FORCE foundation.