Murine models of IDH-wild-type glioblastoma exhibit spatial segregation of tumor initiation and manifestation during evolution

Primary glioblastoma, representing over 90% of adult glioblastoma, develop rapidly without preexisting lower-grade glioma. We have generated a mouse model of primary glioblastoma driven by a single p53 mutation. These p53-mutant gliomas lose the syntenic region of human chromosome 10q, which is mapped to mouse chr19 and chr7. Loss of mouse chr19, containing Pten, activates PI3K/Akt signaling. Using serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building, we showed two distinct types of tumor evolution in p53-mutant driven mouse models. Malignant gliomas/GBMs grew as a single mass (Type 1) and multifocal masses (Type 2), respectively, despite both exhibiting loss of Pten/chromosome 19 (chr19) and PI3K/Akt activation with sub-tetraploid/4N genomes. Analysis of early biopsied and multi-segment tumor tissues revealed no evidence of less proliferative diploid/2N lesions in Type 1 tumors. Strikingly, CA-derived relatively quiescent tumor precursors with ancestral diploid/2N genomes and normal Pten/chr19 were observed in the subventricular zone (SVZ), but was distantly segregated from multi-focal Type 2 tumors. Importantly, PI3K/Akt inhibition by Rictor/mTORC2 deletion blocked distant dispersal, restricting glioma growth in the SVZ. In this study we generate mouse models with single p53 mutations. We profiled the resultant tumors, tumor derived cell lines as well as normal forebrain as controls.

原发性胶质母细胞瘤（Primary glioblastoma）占成人胶质母细胞瘤的90%以上，起病迅速，无既往低级别胶质瘤病史。我们构建了由单一p53突变驱动的原发性胶质母细胞瘤小鼠模型。这类p53突变胶质瘤会丢失与人类10号染色体长臂（10q）同源的小鼠染色体区域，该区域定位于小鼠19号染色体（chr19）和7号染色体（chr7）。包含磷酸酶与张力蛋白同源物（Pten，phosphatase and tensin homolog）的小鼠19号染色体缺失会激活PI3K/Akt信号通路。通过连续磁共振成像（MRI）/三维重建（3D-reconstruction）、全基因组测序（whole-genome sequencing）以及基于光谱核型分析（spectral karyotyping）的单细胞系统发育树构建，我们证实p53突变驱动的小鼠模型中存在两种截然不同的肿瘤演化类型。尽管两类肿瘤均存在Pten/19号染色体缺失以及PI3K/Akt通路激活，且均带有亚四倍体/4N基因组，但恶性胶质瘤/胶质母细胞瘤（GBMs）分别以单肿块（1型）和多灶性肿块（2型）的形式生长。对早期活检及多分段肿瘤组织的分析显示，1型肿瘤中未发现增殖活性较低的二倍体/2N病变。值得注意的是，在侧脑室室管膜下区（SVZ，subventricular zone）中观察到了CA源性的相对静止的肿瘤前体细胞，这类细胞携带祖先源性二倍体/2N基因组且Pten/19号染色体状态正常，但与多灶性2型肿瘤相距较远。重要的是，通过敲除Rictor/mTORC2抑制PI3K/Akt通路可阻断肿瘤的远距离扩散，将胶质瘤生长限制在室管膜下区内。本研究构建了携带单一p53突变的小鼠模型，对由此生成的肿瘤、肿瘤来源细胞系以及作为对照的正常前脑组织进行了全面表征。