Vitamin D Receptor Activation Attenuates Hippo Pathway Effectors and Cell Survival in Metastatic Neuroblastoma.
Vitamin D Receptor Activation Attenuates Hippo Pathway Effectors and Cell Survival in Metastatic Neuroblastoma.
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DOI：
10.1158/1541-7786.mcr-21-0425
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发表时间：
2022-06-03
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高危神经母细胞瘤的存活率仍然很低。大多数复发的患者存在转移性疾病，目前已知的控制扩散到远处的靶向途径很少。我们之前开发了一个转移小鼠模型，以选择具有增强扩散到骨骼和脑的能力的细胞，并基于差异表达基因确定一个签名，这也预测了患者的生存。为了发现新的神经母细胞瘤治疗方法，我们利用连通性图谱确定了可以逆转这种转移转录特征的化合物，并发现维生素D3类似物钙泊三醇是一种选择性地针对转移潜能增强的细胞系的化合物。骨化三醇可通过维生素D受体(VDR)信号转导抑制转移细胞的增殖和存活，增加河马信号通路的负调节因子RASSF2的表达，并降低河马信号通路效应因子YAP和TAZ的水平。RASSF2对于钙泊三醇的作用以及降低YAP/TAZ的水平和核定位是必需的。钙泊三醇治疗后，增强的转移细胞的迁移和YAP/TAZ水平降低，YAP过表达降低了钙泊三醇的敏感性。此外，在体内，过度表达VDR的转移细胞也显示出较低的肿瘤负担。这种新发现的VDR信号和河马通路之间的联系可以为转移性神经母细胞瘤的治疗策略提供参考。
Survival for high-risk neuroblastoma remains poor. Most patients who recur, present with metastatic disease, and few targetable pathways that govern spread to distant sites are currently known. We previously developed a metastatic mouse model to select cells with enhanced ability to spread to the bone and brain and identified a signature based on differentially expressed genes, which also predicted patient survival. To discover new neuroblastoma therapies, we utilized the Connectivity Map to identify compounds that can reverse this metastatic transcriptional signature and found calcipotriol, a Vitamin D3 analog, to be a compound that selectively targets cell lines with enhanced metastatic potential. Calcipotriol treatment of enhanced metastatic, but not parental, cells reduces proliferation and survival via Vitamin D Receptor (VDR) signaling, increases the expression of RASSF2, a negative regulator of the Hippo signaling pathway, and reduces the levels of the Hippo pathway effectors YAP and TAZ. RASSF2 is required for the effects of calcipotriol and for the reduction of levels and nuclear localization of YAP/TAZ. Migration of the enhanced metastatic cells and YAP/TAZ levels are reduced after calcipotriol treatment and YAP overexpression reduces calcipotriol sensitivity. Furthermore, metastatic cells that overexpress VDR also showed lower tumor burden in vivo. This newly identified link between VDR signaling and the Hippo pathway could inform treatment strategies for metastatic neuroblastoma.