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TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth.

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.

SUBMITTER: Sepporta MV

PROVIDER: S-EPMC8755726 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TWIST1 expression is associated with high-risk Neuroblastoma and promotes Primary and Metastatic Tumor Growth

Project description:In this study, merging in silico transcriptomic data and in situ TMA studies, we first highlighted the clinical significance and the value as prognostic factors of the embryonic TFs TWIST1 and TWIST2, thus linking their level of expression with the outcome of NB patients. Secondly, using NB cells knocked out for the TWIST1 protein, we studied the biological impact of TWIST1 in tumors xenografts. The expression of TWIST1 was associated with enhanced primary and secondary tumor growth capacity in immunocompromised mice. Furthermore, tumors expressing TWIST1 were portrayed by a more aggressive phenotype, characterized by the presence of spindle shaped cells and the destruction of the ECM collagen fibers. Finally, the transcriptional signature deregulated by TWIST1 was found to have a clinical significance in human primary tumors and resulted to be able to activate the TME in ortho-derived xenograft. This dataset reports analyses that studied the impact of knockout of the TWIST1 protein on the secretome of the neuroblastoma cell line mentioned above.

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TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth

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TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth

Project description:TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth

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Project description:Simple Summary The tumor metastasis in the bone marrow or other organs in high-risk neuroblastoma patients is a serious problem to tackle and strongly impairs the survival of patients. Novel and effective targets for the treatment of neuroblastoma, especially tumor metastasis, need to be explored. Using multiple databases and analysis methods, LPAR1 was screened out through our comprehensive bioinformatics analysis and found to be positively associated with survival of neuroblastoma patients. LPAR1 was proved to be reduced in neuroblastoma cells compared with non-mailgant cells. LPA-LPAR1 axis showed migration-inhibitory effects on neuroblastoma cells, suggesting that LPAR1 may be a potential target for future treatment of neuroblastoma. Abstract Neuroblastoma is the most common extracranial solid tumor in children. Tumor metastasis in high-risk NB patients is an essential problem that impairs the survival of patients. In this study, we aimed to use a comprehensive bioinformatics analysis to identify differentially expressed genes between NB and control cells, and to explore novel prognostic markers or treatment targets in tumors. In this way, FN1, PIK3R5, LPAR6 and LPAR1 were screened out via KEGG, GO and PPI network analysis, and we verified the expression and function of LPAR1 experimentally. Our research verified the decreased expression of LPAR1 in NB cells, and the tumor migration inhibitory effects of LPA on NB cells via LPAR1. Moreover, knockdown of LPAR1 promoted NB cell migration and abolished the migration-inhibitory effects mediated by LPA-LPAR1. The tumor-suppressing effects of the LPA-LPAR1 axis suggest that LPAR1 might be a potential target for future treatment of NB.

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