Targeting hedgehog signaling reduces self-renewal in embryonal rhabdomyosarcoma.
Targeting hedgehog signaling reduces self-renewal in embryonal rhabdomyosarcoma.
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DOI：
10.1038/onc.2015.267
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发表时间：
2016-04-21
期刊：
影响因子：
8
通讯作者：
Schäfer BW
中科院分区：
文献类型：
--
作者：
Satheesha S;Manzella G;Bovay A;Casanova EA;Bode PK;Belle R;Feuchtgruber S;Jaaks P;Dogan N;Koscielniak E;Schäfer BW
横纹肌肉瘤（RMS）是最常见的儿科软组织癌症，目前的治疗方案依赖于常规化疗，尽管它们显示出临床益处，但在以后的生活中存在不良副作用和继发性肿瘤的显著风险。因此，识别和靶向具有较高致瘤潜力和自我更新能力的亚群将提供改进的患者管理策略。Hedgehog信号已经通过小鼠遗传学和罕见的人类综合征与胚胎性RMS（ERMS）的发展相关联。然而，在散发性RMS中，该途径的激活突变是罕见的，因此hedgehog信号对肿瘤发生的贡献仍不清楚。在这里，我们通过遗传丧失和功能获得实验以及临床相关小分子调节剂的使用表明，刺猬信号对于控制RMS细胞亚群的体外自我更新和体内肿瘤起始是重要的。此外，hedgehog活性改变了化学抗性、运动性和分化状态。核心干细胞基因NANOG被确定为对ERMS自我更新很重要，可能作用于hedgehog信号传导的下游。至关重要的是，评估患者活检组织中通过GLI1和NANOG表达鉴定的肿瘤增殖细胞亚群的存在具有预后意义。因此，这项工作确定了ERMS中hedgehog信号传导的新功能方面，重新定义了其靶向控制ERMS自我更新的基本原理，并强调了研究儿科癌症中功能性肿瘤异质性的重要性。
Current treatment regimens for rhabdomyosarcoma (RMS), the most common pediatric soft tissue cancer, rely on conventional chemotherapy, and although they show clinical benefit, there is a significant risk of adverse side effects and secondary tumors later in life. Therefore, identifying and targeting sub-populations with higher tumorigenic potential and self-renewing capacity would offer improved patient management strategies. Hedgehog signaling has been linked to the development of embryonal RMS (ERMS) through mouse genetics and rare human syndromes. However, activating mutations in this pathway in sporadic RMS are rare and therefore the contribution of hedgehog signaling to oncogenesis remains unclear. Here, we show by genetic loss- and gain-of-function experiments and the use of clinically relevant small molecule modulators that hedgehog signaling is important for controlling self-renewal of a subpopulation of RMS cells in vitro and tumor initiation in vivo. In addition, hedgehog activity altered chemoresistance, motility and differentiation status. The core stem cell gene NANOG was determined to be important for ERMS self-renewal, possibly acting downstream of hedgehog signaling. Crucially, evaluating the presence of a subpopulation of tumor-propagating cells in patient biopsies identified by GLI1 and NANOG expression had prognostic significance. Hence, this work identifies novel functional aspects of hedgehog signaling in ERMS, redefines the rationale for its targeting as means to control ERMS self-renewal and underscores the importance of studying functional tumor heterogeneity in pediatric cancers.