Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Nat Commun. 2020 Dec 18;11(1):6434. doi: 10.1038/s41467-020-20225-w.
Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis. Here, we perform multi-omic profiling of 60 glioblastoma primary tumours and use orthogonal analysis of chromatin and RNA-derived gene regulatory networks to identify 38 subtype master regulators, whose cell population-specific activities we further map in published single-cell RNA sequencing data. These analyses identify the oligodendrocyte precursor marker and chromatin modifier SOX10 as a master regulator in RTK I-subtype tumours. In vitro functional studies demonstrate that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. SOX10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects.
胶质母细胞瘤经常表现出与治疗相关的向间充质表型的亚型转变，预后不良。在这里，我们对 60 个胶质母细胞瘤原发肿瘤进行了多组学分析，并使用染色质和 RNA 衍生的基因调控网络的正交分析来鉴定 38 个亚型主调控因子，我们进一步在已发表的单细胞 RNA 测序数据中对其细胞群体特异性活性进行了映射。这些分析确定少突胶质前体细胞标记物和染色质修饰因子 SOX10 是 RTK I 亚型肿瘤的主调控因子。体外功能研究表明，SOX10 的缺失导致类似于患者在转录组、表观遗传和表型水平上观察到的前体细胞-间充质转化的亚型转换。SOX10 在体内同源移植胶质母细胞瘤小鼠模型中的抑制导致肿瘤侵袭增加、免疫细胞浸润和存活率显著降低，类似于进行性人类胶质母细胞瘤。这些结果表明 SOX10 是 RTK I 亚型的真正主调控因子，具有肿瘤细胞内在和微环境的双重作用。
