Abstract
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 colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display 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.
Highlights
The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes
Since TWIST1/2 are active in neural crest (NC) cells, where they play a key role in driving epithelial to mesenchymal transition (EMT) and migration, the study of their functions in NB is important to better understand the neuroblastomagenesis, as distant metastases are already present by the time of diagnosis for the disseminated forms of this disease
Using an in vivo model for transcriptomic analyses, we unveiled the impact of CRISPR/Cas9-mediated TWIST1 silencing on NB tumor growth, metastatic colonization, and the reorganization of the tumor microenvironment (TME)
Summary
The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. We investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. 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. Reactivation and aberrant functions of TWIST1/2 have been found in several carcinomas Both TFs provide cells with critical properties including self-renewal capabilities, resistance to oncogene-induced failsafe programs, and invasive capabilities promoting cancer initiation and progression toward a metastatic disease[10,11,13]. Using an in vivo model for transcriptomic analyses, we unveiled the impact of CRISPR/Cas9-mediated TWIST1 silencing on NB tumor growth, metastatic colonization, and the reorganization of the tumor microenvironment (TME)
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