Nguyen Lien D, Sengupta Satyaki, Cho Kevin I, Floru Alexander, George Rani E, Krichevsky Anna M
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA.
Sci Signal. 2025 Apr 15;18(882):eads2641. doi: 10.1126/scisignal.ads2641.
Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest-derived progenitor cells, presents clinical challenges. Unlike adrenergic (ADRN) neuroblastoma cells, neuroblastoma cells with a mesenchymal (MES) identity are resistant to chemotherapy and retinoid therapy, which contributes to relapses and treatment failures. We explored whether up-regulation of the neurogenic, tumor suppressor microRNA miR-124 could promote the differentiation of retinoic acid-resistant MES neuroblastoma cells. Leveraging our screen for miRNA-modulatory small molecules, we identified and validated the tyrosine and phosphoinositide kinase inhibitor PP121 as a robust inducer of miR-124. Combining PP121 and BDNF-activating bufalin synergistically arrested proliferation and promoted the sustained differentiation of MES/heterogeneous SK-N-AS cells over several weeks. This protocol also resulted in the differentiation of multiple MES neuroblastoma and glioblastoma cell lines. RNA-seq analysis of differentiated MES/heterogeneous SK-N-AS cells revealed the replacement of the ADRN core regulatory circuitry with circuitries associated with chromaffin cells and Schwann cell precursors. Furthermore, differentiation was associated with inhibition of the CDK4/CDK6 pathway and activation of a transcriptional program that correlated with improved outcomes for patients with neuroblastoma. Our findings suggest an approach with translational potential to induce the differentiation of therapy-resistant cancers of the nervous system. Moreover, these long-lived, differentiated cells could be used to study mechanisms underlying cancer biology and therapies.
神经母细胞瘤是一种起源于神经嵴衍生祖细胞的儿童癌症，其肿瘤细胞异质性带来了临床挑战。与肾上腺素能（ADRN）神经母细胞瘤细胞不同，具有间充质（MES）特征的神经母细胞瘤细胞对化疗和维甲酸治疗具有抗性，这导致了复发和治疗失败。我们探究了神经源性肿瘤抑制性微小RNA miR-124的上调是否能促进视黄酸抗性MES神经母细胞瘤细胞的分化。利用我们对miRNA调节小分子的筛选，我们鉴定并验证了酪氨酸和磷酸肌醇激酶抑制剂PP121是miR-124的强力诱导剂。将PP121和激活BDNF的蟾毒灵联合使用，在数周内协同抑制了增殖并促进了MES/异质性SK-N-AS细胞的持续分化。该方案还导致了多种MES神经母细胞瘤和胶质母细胞瘤细胞系的分化。对分化后的MES/异质性SK-N-AS细胞进行RNA测序分析发现，ADRN核心调控电路被与嗜铬细胞和雪旺细胞前体相关的电路所取代。此外，分化与CDK4/CDK_{6}通路的抑制以及与神经母细胞瘤患者更好预后相关的转录程序的激活有关。我们的研究结果提示了一种具有转化潜力的方法，可诱导耐药性神经系统癌症的分化。此外，这些长期存活的分化细胞可用于研究癌症生物学和治疗的潜在机制。
