Filipponi Doria, Pagnuzzi-Boncompagni Marina, Pagès Gilles
Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco.
LIA ROPSE, Laboratoire International Associé Université Côte d'Azur-Centre Scientifique de Monaco, 06100 Nice, France.
Cancers (Basel). 2022 Apr 22;14(9):2095. doi: 10.3390/cancers14092095.
Medulloblastoma (MB) is a malignant pediatric brain tumor, and it represents the leading cause of death related to cancer in childhood. New perspectives for therapeutic development have emerged with the identification of cancer stem cells (CSCs) displaying tumor initiating capability and chemoresistance. However, the mechanisms responsible for CSCs maintenance are poorly understood. The lack of a universal marker signature represents the main constraints to identify and isolate CSCs within the tumor.
To identify signaling pathways promoting CSC maintenance in MB, we combined tumorsphere assays with targeted neurogenesis PCR pathway arrays.
We showed a consistent induction of signaling pathways regulating pluripotency of CSCs in all the screened MB cells. BMP4 signaling was consistently enriched in all tumorsphere(s) independently of their specific stem-cell marker profile. The octamer-binding transcription factor 4 (OCT4), an important regulator of embryonic pluripotency, enhanced CSC maintenance in MBs by inducing the BMP4 signaling pathway. Consistently, inhibition of BMP4 signaling with LDN-193189 reduced stem-cell traits and promoted cell differentiation.
Our work suggests that interfering with the BMP4 signaling pathway impaired the maintenance of the CSC pool by promoting cell differentiation. Hence, differentiation therapy might represent an innovative therapeutic to improve the current standard of care in MB patients.
髓母细胞瘤（MB）是一种儿童恶性脑肿瘤，是儿童癌症相关死亡的主要原因。随着具有肿瘤起始能力和化疗耐药性的癌症干细胞（CSCs）的发现，治疗发展出现了新的视角。然而，负责CSCs维持的机制仍知之甚少。缺乏通用的标志物特征是在肿瘤内识别和分离CSCs的主要限制。
为了识别促进MB中CSC维持的信号通路，我们将肿瘤球分析与靶向神经发生PCR通路阵列相结合。
我们发现在所有筛选的MB细胞中，调节CSCs多能性的信号通路均有一致的诱导。BMP4信号通路在所有肿瘤球中均持续富集，与它们特定的干细胞标志物谱无关。八聚体结合转录因子4（OCT4）是胚胎多能性的重要调节因子，通过诱导BMP4信号通路增强了MB中CSC的维持。同样，用LDN-193189抑制BMP4信号通路可降低干细胞特征并促进细胞分化。
我们的工作表明，干扰BMP4信号通路会通过促进细胞分化而损害CSC池的维持。因此，分化疗法可能是一种创新疗法，可改善MB患者的当前护理标准。
