Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Texas.
Cancer Res. 2023 Mar 15;83(6):890-905. doi: 10.1158/0008-5472.CAN-22-1577.
Malignant gliomas such as glioblastoma are highly heterogeneous with distinct cells of origin and varied genetic alterations. It remains elusive whether the specific states of neural cell lineages are differentially susceptible to distinct genetic alterations during malignant transformation. Here, an analysis of The Cancer Genome Atlas databases revealed that comutations of PTEN and TP53 are most significantly enriched in human high-grade gliomas. Therefore, we selectively ablated Pten and Trp53 in different progenitors to determine which cell lineage states are susceptible to malignant transformation. Mice with PTEN/p53 ablation mediated by multilineage-expressing human GFAP (hGFAP) promoter-driven Cre developed glioma but with incomplete penetrance and long latency. Unexpectedly, ablation of Pten and Trp53 in Nestin+ neural stem cells (NSC) or Pdgfra+/NG2+ committed oligodendrocyte precursor cells (OPC), two major cells of origin in glioma, did not induce glioma formation in mice. Strikingly, mice lacking Pten and Trp53 in Olig1+/Olig2+ intermediate precursors (pri-OPC) prior to the committed OPCs developed high-grade gliomas with 100% penetrance and short latency. The resulting tumors exhibited distinct tumor phenotypes and drug sensitivities from NSC- or OPC-derived glioma subtypes. Integrated transcriptomic and epigenomic analyses revealed that PTEN/p53-loss induced activation of oncogenic pathways, including HIPPO-YAP and PI3K signaling, to promote malignant transformation. Targeting the core regulatory circuitries YAP and PI3K signaling effectively inhibited tumor cell growth. Thus, our multicell state in vivo mutagenesis analyses suggests that transit-amplifying states of Olig1/2 intermediate lineage precursors are predisposed to PTEN/p53-loss-induced transformation and gliomagenesis, pointing to subtype-specific treatment strategies for gliomas with distinct genetic alterations.
Multiple progenitor-state mutagenesis reveal that Olig1/2-expressing intermediate precursors are highly susceptible to PTEN/p53-loss-mediated transformation and impart differential drug sensitivity, indicating tumor-initiating cell states and genetic drivers dictate glioma phenotypes and drug responses. See related commentary by Zamler and Hu, p. 807.
恶性神经胶质瘤（如胶质母细胞瘤）具有高度异质性，具有不同的起源细胞和不同的遗传改变。在恶性转化过程中，特定的神经细胞谱系状态是否容易受到不同的遗传改变，目前仍不清楚。在这里，对癌症基因组图谱数据库的分析表明，PTEN 和 TP53 的共突变在人类高级别神经胶质瘤中最为丰富。因此，我们选择性地在不同的祖细胞中敲除 Pten 和 Trp53，以确定哪些细胞谱系状态容易发生恶性转化。由多谱系表达的人 GFAP（hGFAP）启动子驱动 Cre 介导的 Pten/p53 敲除的小鼠发展为神经胶质瘤，但不完全穿透和潜伏期长。出乎意料的是，在神经干/祖细胞（NSC）或 PDGFRa+/NG2+ 少突胶质前体细胞（OPC）中敲除 Pten 和 Trp53，这两种神经胶质瘤的主要起源细胞，不会在小鼠中诱导神经胶质瘤的形成。引人注目的是，在 Olig1+/Olig2+ 中间前体细胞（pri-OPC）中敲除 Pten 和 Trp53，而不是在定向 OPC 之前，导致高级别神经胶质瘤的形成，其穿透率为 100%，潜伏期短。由此产生的肿瘤表现出与 NSC 或 OPC 衍生的神经胶质瘤亚型不同的肿瘤表型和药物敏感性。整合转录组和表观基因组分析表明，PTEN/p53 缺失诱导了致癌途径的激活，包括 HIPPO-YAP 和 PI3K 信号通路，以促进恶性转化。靶向核心调控电路 YAP 和 PI3K 信号通路可有效抑制肿瘤细胞生长。因此，我们的体内多细胞状态诱变分析表明，Olig1/2 中间谱系前体细胞的过渡扩增状态易受 PTEN/p53 缺失诱导的转化和神经胶质瘤发生的影响，这为具有不同遗传改变的神经胶质瘤提供了特定于亚型的治疗策略。
多祖细胞状态诱变揭示了 Olig1/2 表达的中间前体细胞对 PTEN/p53 缺失介导的转化高度敏感，并赋予了不同的药物敏感性，表明起始肿瘤细胞状态和遗传驱动因素决定了神经胶质瘤的表型和药物反应。请参阅 Hu 和 Zamler 的相关评论，第 807 页。
