Mutations in Sonic hedgehog (SHH) signaling promote aberrant proliferation and tumor growth. SHH-medulloblastoma (MB) is among the most frequent brain tumors in children less than 3 years of age. Although key components of the SHH pathway are well-known, we hypothesized that new disease-modifying targets of SHH-MB might be identified from large-scale bioinformatics and systems biology analyses. Using a data-driven systems biology approach, we built a MB-specific interactome. The ATP-binding cassette transporter ABCC4 was identified as a modulator of SHH-MB. Accordingly, increased ABCC4 expression correlated with poor overall survival in patients with SHH-MB. Knockdown of ABCC4 expression markedly blunted the constitutive activation of the SHH pathway secondary to Ptch1 or Sufu insufficiency. In human tumor cell lines, ABCC4 knockdown and inhibition reduced full-length GLI3 levels. In a clinically relevant murine SHH-MB model, targeted ablation of Abcc4 in primary tumors significantly reduced tumor burden and extended the lifespan of tumor-bearing mice. These studies reveal ABCC4 as a potent SHH pathway regulator and a new candidate to target with the potential to improve SHH-MB therapy. SIGNIFICANCE: These findings identify ABCC4 transporter as a new target in SHH-MB, prompting the development of inhibitors or the repurporsing of existing drugs to target ABCC4.

中文翻译：

---

ABC转运蛋白通过调节声波刺猬信号来驱动髓母细胞瘤的发病机理。

声波刺猬（SHH）信号的突变促进异常增殖和肿瘤生长。SHH髓母细胞瘤（MB）是3岁以下儿童中最常见的脑肿瘤之一。尽管SHH途径的关键组成部分是众所周知的，但我们假设可以从大规模生物信息学和系统生物学分析中确定新的改变SHH-MB的疾病目标。使用数据驱动的系统生物学方法，我们构建了特定于MB的交互基因组。ATP结合盒转运蛋白ABCC4被确定为SHH-MB的调节剂。因此，SHH-MB患者的ABCC4表达增加与总生存期差有关。击倒ABCC4表达明显削弱了继Ptch1或Sufu功能不全的SHH途径的组成型激活。在人类肿瘤细胞系中 ABCC4敲低和抑制降低了全长GLI3水平。在临床相关的鼠类SHH-MB模型中，在原发性肿瘤中靶向消融Abcc4可显着降低肿瘤负荷并延长荷瘤小鼠的寿命。这些研究表明，ABCC4是一种有效的SHH途径调节剂，是一种有潜力改善SHH-MB治疗的新靶标。意义：这些发现确定ABCC4转运蛋白是SHH-MB的新靶标，促使开发抑制剂或将现有药物重新购回以靶向ABCC4。这些研究表明，ABCC4是一种有效的SHH途径调节剂，是一种有潜力改善SHH-MB治疗的新靶标。意义：这些发现确定ABCC4转运蛋白是SHH-MB的新靶标，促使开发抑制剂或将现有药物重新购回以靶向ABCC4。这些研究表明，ABCC4是一种有效的SHH途径调节剂，是一种有潜力改善SHH-MB治疗的新靶标。意义：这些发现确定ABCC4转运蛋白是SHH-MB的新靶标，促使开发抑制剂或将现有药物重新购回以靶向ABCC4。