Comer Charley, Cotton Kian, Edwards Christopher, Dai Xiaoyang, Badodi Sara, Buccafusca Roberto, Bennett Chris, Peet Andrew, Williams Alice, Michod David, Bochukova Elena, Niklison-Chirou Maria Victoria
Life Science Department, University of Bath, Bath, UK.
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Cell Death Dis. 2025 Jul 15;16(1):527. doi: 10.1038/s41419-025-07829-0.
Medulloblastomas (MBs) are aggressive brain cancers and represent the most common primary malignant tumour in children. Current treatment protocols involve an intensive regimen of surgery, radiation therapy and chemotherapy, guided by histopathology and risk stratification. Unfortunately, disease relapse proves fatal in 30% of cases, and treatment efficacy is compromised as MB cells develop resistance. Therefore, there is a critical need for more effective and tolerable therapies, especially for the treatment of aggressive MBs associated with a poor prognosis. Lipid metabolism reprogramming, characterized by increased cholesterol synthesis, lipid uptake and the activation of de novo lipogenesis, is a newly identified hallmark of cancers. Cholesterol is an essential structural component of membranes that contributes to membrane integrity and fluidity. Recently, increasing evidence has indicated that cholesterol is a major determinant by modulating cell signalling events governing the hallmarks of cancer. Our research demonstrates there is an overexpression of cholesterol metabolism in group 3 (G3), and group 4 (G4) MB subgroups compared to Sonic Hedgehog (SHH)-MB subgroup. In these tumours, cholesterol metabolism supports cell migration through the Rho-GTPase signalling pathway. Notably, we observed that shifting the culture conditions from 2D to 3D significantly upregulates lipid metabolism. Furthermore, spheroids derived from G3/G4-MBs and SHH-MBs show similar sensitivity to low doses of simvastatin. We validated these findings in a xenograft mouse model, where treatment with low doses of simvastatin led to increased survival time and remarkably, also reduced the metastatic spread of MB cells to the spinal cord. These results suggest that simvastatin holds potential as an adjuvant treatment for patients with medulloblastoma.
髓母细胞瘤（MBs）是侵袭性脑癌，也是儿童中最常见的原发性恶性肿瘤。目前的治疗方案包括在组织病理学和风险分层的指导下，进行手术、放射治疗和化疗的强化疗程。不幸的是，30%的病例疾病复发被证明是致命的，并且随着MB细胞产生耐药性，治疗效果受到损害。因此，迫切需要更有效且耐受性更好的疗法，特别是用于治疗预后不良的侵袭性MBs。脂质代谢重编程，其特征为胆固醇合成增加、脂质摄取增加以及从头脂肪生成的激活，是新发现的癌症标志。胆固醇是膜的重要结构成分，有助于维持膜的完整性和流动性。最近，越来越多的证据表明，胆固醇是通过调节控制癌症标志的细胞信号事件的主要决定因素。我们的研究表明，与 Sonic Hedgehog（SHH）-MB 亚组相比，3 组（G3）和 4 组（G4）MB 亚组中胆固醇代谢存在过表达。在这些肿瘤中，胆固醇代谢通过 Rho-GTPase 信号通路支持细胞迁移。值得注意的是，我们观察到将培养条件从二维转变为三维会显著上调脂质代谢。此外，源自 G3/G4-MBs 和 SHH-MBs 的球体对低剂量辛伐他汀表现出相似的敏感性。我们在异种移植小鼠模型中验证了这些发现，低剂量辛伐他汀治疗导致存活时间延长，并且显著减少了 MB 细胞向脊髓的转移扩散。这些结果表明辛伐他汀有望作为髓母细胞瘤患者的辅助治疗药物。
