ERBB-STAT3 轴驱动袋獾面部肿瘤疾病。
The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.
机构信息
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
出版信息
Cancer Cell. 2019 Jan 14;35(1):125-139.e9. doi: 10.1016/j.ccell.2018.11.018.
The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. VIDEO ABSTRACT.
由于传染性袋獾面部肿瘤疾病（DFTD）的影响，有袋动物袋獾（Sarcophilus harrisii）面临灭绝的威胁。为了揭示这种传染性癌症的分子基础，我们将药理学筛选与综合系统生物学特征相结合。对表皮生长因子受体酪氨酸激酶抑制剂的敏感性与其过表达相关。蛋白质组学和 DNA 甲基化分析揭示了与进化保守的致癌 STAT3 相关的肿瘤特异性特征。表皮生长因子受体酪氨酸激酶抑制可阻断 STAT3 的磷酸化并阻止癌细胞生长。在异种移植模型中，表皮生长因子受体酪氨酸激酶或 STAT3 的药理学阻断可阻止肿瘤生长，并恢复 MHC Ⅰ类的表达。这种过度活跃的 ERBB-STAT3 轴与主要组织相容性复合体Ⅰ介导的肿瘤免疫监视之间的联系，为水平传播提供了机制上的见解，并提出了一种双重化疗免疫治疗策略，以挽救袋獾免受 DFTD 的影响。视频摘要。
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