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Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N6-methyladenosine (m6A) epitranscriptomic modification controls post-transcriptional gene expression but the mechanism by which the m6A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m6A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCC. We demonstrate that the m6A modification regulates the expression of HOX genes in tNCC, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posterior HOX genes are m6A modified in MYCN-amplified NB with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes creating an undifferentiated state. Moreover, METTL3 depletion/inhibition induces DNA damage and differentiation of MYCN overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts (PDX) in vivo, suggesting METTL3 inhibition could be a potential therapeutic approach for NB. Synopsis: Neuroblastoma (NB) childhood cancers, associated with amplification of the MYCN oncogene, present an undifferentiated phenotype and are challenging to treat. This study reports MYCN cooperation with the m6A methyltransferase METTL3 promoting epitranscriptome changes and a developmental, aggressive state in early trunk neural crest cells (tNCC). m6A deposition regulatesHOX gene expression in tNCC, ensuring their proper differentiation into sympathetic neurons. Increased MYCN levels promote METTL3 recruitment and m6A deposition at specific genes in tNCC, including HOX genes, which maintain an undifferentiated state in NB. Depleting or inhibiting METTL3 in MYCN-driven NB promotes cell differentiation and triggers DNA damage. Inhibiting METTL3 increases NB sensitivity to chemotherapy in mice. MYCN oncogene drives METTL3 recruitment and m6A deposition at posterior HOX genes, creating an undifferentiated state in early neural crest cells. [ABSTRACT FROM AUTHOR]

Age, tumor grade, and mitosis-karyorrhexis index (MKI) are independently predictive of outcome in neuroblastoma (NB). Transcriptomic analysis of the 4SC-205-treated tumors confirmed the expected genetic changes of arrested cells in mitosis and tumor cells with reduced proliferation or viability (Figure 2M-O). The oral KIF11 inhibitor 4SC-205 exhibits antitumor activity and potentiates standard and targeted therapies in primary and metastatic neuroblastoma models Mice treated with 4SC-205 presented small tumors located in the adrenal gland, whereas vehicle-treated mice had large tumors with the kidney completely surrounded by the tumor (Figure 3G). [Extracted from the article]

Tumors are complex networks of constantly interacting elements: tumor cells, stromal cells, immune and stem cells, blood/lympathic vessels, nerve fibers and extracellular matrix components. These elements can influence their microenvironment through mechanical and physical signals to promote tumor cell growth. To get a better understanding of tumor biology, cooperation between multidisciplinary fields is needed. Diverse mathematic computations and algorithms have been designed to find prognostic targets and enhance diagnostic assessment. In this work, we use computational digital tools to study the topology of vitronectin, a glycoprotein of the extracellular matrix. Vitronectin is linked to angiogenesis and migration, two processes closely related to tumor cell spread. Here, we investigate whether the distribution of this molecule in the tumor stroma may confer mechanical properties affecting neuroblastoma aggressiveness. Combining image analysis and graph theory, we analyze different topological features that capture the organizational cues of vitronectin in histopathological images taken from human samples. We find that the Euler number and the branching of territorial vitronectin, two topological features, could allow for a more precise pretreatment risk stratification to guide treatment strategies in neuroblastoma patients. A large amount of recently synthesized VN would create migration tracks, pinpointed by both topological features, for malignant neuroblasts, so that dramatic change in the extracellular matrix would increase tumor aggressiveness and worsen patient outcomes. What's new? The tumor microenvironment has a strong influence on cancer malignancy. Here, the authors investigate whether the organization of the extracellular matrix glycoprotein vitronectin in the tumor stroma may confer mechanical properties affecting neuroblastoma aggressiveness. Combining image analysis and graph theory, they identify two topological features of vitronectin that could potentially be used to improve patient pre‐treatment risk stratification. The data also point to the creation of vitronectin migration tracks for malignant neuroblasts, so that dramatic changes in the extracellular matrix would increase tumor stiffness and aggressiveness and worsen patient outcomes. [ABSTRACT FROM AUTHOR]