The study of underlying mechanism of EGFR-Ras signaling in glioblastoma

高级别星形细胞瘤（HGA）仍然致命，没有有效的治疗。使用一个可诱导Cre驱动的成体星形胶质细胞特异性系统，我们探讨了在人类胶质母细胞瘤（IV级; GBM）中干扰的关键通路在HGA的启动和进展中的相对作用。可能的事件组合（工程和自发）产生的疾病表明每种畸变的等级特异性作用，并提示从II级[仅由pRb-肿瘤抑制（TS）灭活诱导]到III级的特定进展机制（添加KrasG 12 D激活，通过突变或错误定位自发失活p53），至IV级[进一步增加PTEN失活（自发或工程化）]而无IDH 1突变。在从II级到III级疾病的转变中以及随后的KrasG 12 D激活中，Trp 53错义突变与人GBM突变一致。这项研究强调了具有明显肿瘤异质性的随机事件的重要性，以概括疾病的性质。重要的是，小鼠GBM转录组显示出与高度侵袭性的人间充质GBM亚类的一致性。为了确定EGFR是否在我们的星形细胞瘤小鼠模型（具有Rb-TS失活和KrasG 12 D活化（TR模型））中的肿瘤进展中发挥作用，我们对TR肿瘤进行免疫组织化学（IHC）研究和FISH分析，发现EGFR扩增/过表达。EGFR抑制剂厄洛替尼对EGFR的抑制在体内和体外对TR肿瘤显示出耐药性，这与人类临床数据一致。然而，这些肿瘤在体外显示出对多种RTK抑制剂的敏感性，表明其他RTK可以补偿单一EGFR抑制。我们目前正在进行分子途径分析，以剖析EGFR抑制的代偿机制。Song Y，Zhang Q，Bash R，Kutlu B，Difilippantonio S，Yin C，吉尔伯特D，Wang C，Yang C，Bullitt E，Kafri T，McCarthy [10]李国伟，米勒，货车戴克.胶质母细胞瘤的进化路径：从工程小鼠的病因学洞察。（转载自Cancer Discovery）

High grade astrocytomas (HGA) remain fatal without effective treatment. Using an inducible Cre-driven adult astrocyte-specific system, we explored the relative roles of key pathways perturbed in human glioblastomas (grade IV; GBM) in initiation and progression of HGA. The likely event combinations (engineered and spontaneous) yielding disease indicate grade-specific roles for each aberration and suggest specific progression mechanisms from grade II [induced only by pRb-tumor suppression (TS) inactivation] to III (addition of KrasG12D activation, with spontaneous inactivation of p53 by mutation or mislocalization), to Grade IV [further addition of PTEN inactivation (spontaneous or engineered)] without IDH1 mutation. In the transition from grade II to III disease and subsequent to KrasG12D activation, Trp53 missense mutations congruent with human GBM mutations. This study underscores the importance of stochastic events with evident tumor heterogeneity in order to recapitulate disease properties. Importantly, murine GBM transcriptomes showed concordance with the highly aggressive human mesenchymal GBM subclass.To determine whether EGFR played a role on tumor progression in our astrocytoma mouse model with inactivation of Rb-TS and activation of KrasG12D (TR model), we performed immunohistochemistry (IHC) study and FISH analysis on TR tumors, and found that EGFR was amplified/overexpressed. Inhibition of EGFR by EGFR inhibitor Erlotinib showed resistance in vivo and in vitro on TR tumors, which is consistent with the human clinical data. However, these tumors showed sensitivity to multiple RTK inhibitors in vitro, indicating that other RTKs may compensate for single EGFR inhibition. We are currently working on molecular pathway analysis to dissect the compensatory mechanism of EGFR inhibition. Song Y, Zhang Q, Bash R, Kutlu B, Difilippantonio S, Yin C, Gilbert D, Wang C, Yang C, Bullitt E, Kafri T, McCarthy K, Louis D, Hood L, Miller CR, Van Dyke T. An evolutionary path to glioblastoma: Insight into etiology from engineered mice. (Under review at Cancer Discovery)