Sancho-Martinez Ignacio, Nivet Emmanuel, Xia Yun, Hishida Tomoaki, Aguirre Aitor, Ocampo Alejandro, Ma Li, Morey Robert, Krause Marie N, Zembrzycki Andreas, Ansorge Olaf, Vazquez-Ferrer Eric, Dubova Ilir, Reddy Pradeep, Lam David, Hishida Yuriko, Wu Min-Zu, Esteban Concepcion Rodriguez, O'Leary Dennis, Wahl Geoffrey M, Verma Inder M, Laurent Louise C, Izpisua Belmonte Juan Carlos
Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, N° 135 Guadalupe, Murcia 30107, Spain.
Nat Commun. 2016 Feb 22;7:10743. doi: 10.1038/ncomms10743.
Glioma tumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs). Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use of human embryonic material. Recently, the somatic genomic landscape of human gliomas has been reported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in ∼90% and 86% of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotent stem cells (hiPSCs) for modelling gliomagenesis. Dysregulation of RTK and p53 signalling in hiPSC-derived NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo transplantation of transformed iNPCs leads to highly aggressive tumours containing undifferentiated stem cells and their differentiated derivatives. Metabolic modulation compromises GTIC viability. Last, screening of 101 anti-cancer compounds identifies three molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results highlight the potential of hiPSCs for studying human tumourigenesis.
胶质瘤肿瘤起始细胞（GTICs）可起源于神经祖细胞（NPCs）的转化。对GTICs的研究主要集中在可从中分离出GTICs的原发性肿瘤以及人类胚胎材料的使用上。最近，已报道了人类胶质瘤的体细胞基因组图谱。在所有分析的原发性肿瘤中，分别约有90%和86%的肿瘤中发现受体酪氨酸激酶（RTK）和p53信号通路失调。在此，我们报告了利用人类诱导多能干细胞（hiPSCs）建立胶质瘤发生模型的情况。hiPSC来源的NPCs（iNPCs）中RTK和p53信号通路的失调在体外重现了GTICs的特性。转化后的iNPCs的体内移植会导致产生含有未分化干细胞及其分化衍生物的高度侵袭性肿瘤。代谢调节会损害GTICs的活力。最后，对101种抗癌化合物的筛选鉴定出了三种特异性靶向转化后的iNPCs和原发性GTICs的分子。总之，我们的结果突出了hiPSCs在研究人类肿瘤发生方面的潜力。
