Pathological epigenetic hyper-plasticity promotes acquisition of pro-tumor states in cancer

项目总结 本次K22 NCI转型职业发展奖的候选人是博士后威廉·弗拉瓦汉博士 马萨诸塞州总医院和布罗德研究所研究员。该奖项的重点是弗拉瓦汉博士的长期- 任期目标是成为一名研究癌症表观遗传学的独立研究员。表观遗传学是基础 控制细胞身份、执行转录程序和驱动细胞表型的机制。 表观遗传过程在癌症中经常改变，并可能作为肿瘤形成的启动事件， 推动细胞身份的恶性转化。表观遗传过程经过严格校准，允许 为细胞分化或响应等过程设置细胞身份识别程序 外部刺激。在弗拉瓦汉博士之前工作的基础上，附上的应用程序试图检验这一假说 癌症特异性表观遗传超塑性形成了肿瘤特异性调控机制的基础 逃避和转变。该应用程序建议测试的生物环境是琥珀酸 脱氢酶(SDH)缺陷型胃肠道间质瘤(GIST)。虽然GIST的大多数人都有 原癌基因KIT中的一种突变，临床上对KIT抑制高度敏感，SDH缺陷的GIST是 抵抗大多数形式的治疗。此应用程序提供的初步数据表明，主要的 肿瘤转化的机制与弗拉瓦汉博士之前描述的丢失 表观绝缘层保护癌基因免受有效的家务超级增强剂的影响。这些数据表明 在SDH缺乏的GIST中，绝缘子的丢失激活了成纤维细胞生长因子配体基因，以及患者来源的异种移植 这种疾病的模型对FGFR靶向治疗高度敏感。此应用程序寻求首先测试 表观遗传可塑性是这些肿瘤转化和易感性的假说 抑制FGFR，并可能导致对相同治疗的耐药性。其次，这个应用程序试图深入研究 利用表观遗传遗传和等位基因模型-- 具体询问临床患者切除时，绝缘层的丢失发生在肿瘤起始时，并可能 SDH缺陷GIST背后的司机损害。该应用程序将利用尖端的表观遗传学分析 以及先进的细胞培养工程和疾病的异种移植模型。此应用程序的主要关注点是 了解使癌细胞能够驱动疾病的基本表观遗传过程，希望 创造洞察力，以便进行治疗靶向和治疗。作为潜在的表观遗传状态 造成这种损害(DNA超甲基化)在癌症中很常见，这些项目的结果可能会 GIST之外的重大相关性。

PROJECT SUMMARY The candidate for this K22 NCI Transition Career Development Award is Dr. William Flavahan, a postdoctoral fellow at Massachusetts General Hospital and the Broad Institute. This award focuses on Dr. Flavahan’s long- term goal of becoming an independent investigator studying cancer epigenetics. Epigenetics are the fundamental mechanisms that control cell identity, enforcing the transcriptional programs and driving cellular phenotypes. Epigenetic processes are frequently altered in cancer, and may serve as initiating events for tumor formation, driving malignant transformation of the cellular identity. Epigenetic processes are tightly calibrated, allowing transitions along set cellular identity programs for processes such as cellular differentiation or response to external stimuli. Building on Dr. Flavahan’s previous work, the enclosed application seeks to test the hypothesis that cancer-specific epigenetic hyperplasticity forms the basis of a tumor-specific mechanism of regulatory evasion and transformation. The biological setting this application proposes to test is that of succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST). While the majority of GIST present with a mutation in the oncogene KIT and are highly clinically responsive to KIT inhibition, SDH-deficient GIST are resistant to most forms of therapy. This application presents preliminary data showing that the primary mechanism of tumor transformation is identical to Dr. Flavahan’s previously described paradigm of loss of epigenetic insulation protecting an oncogene from a potent housekeeping superenhancer. These data show that in SDH-deficient GIST, loss of an insulator activates FGF ligand genes, and a patient-derived xenograft model of this disease is highly responsive to FGFR-targeted therapy. This application seeks to first test the hypothesis that epigenetic plasticity is responsible for the transformation and vulnerability of these tumors to FGFR inhibition and that it may drive resistance to the same treatment. Second, this application seeks to delve into the underpinnings of the epigenetic lesion to demonstrate, using models of epigenetic inheritance and allele- specific interrogation of clinical patient resection, that the loss of insulation occurs at tumor initiation and may be the driver lesion behind SDH-deficient GIST. The application will leverage cutting edge epigenetic assays as well as advanced cell culture engineering and xenograft models of disease. The main focus of this application is to understand the fundamental epigenetic processes that enable cancer cells to drive the disease and hopefully create insight that will allow for therapeutic targeting and treatment. As the underlying epigenetic state that creates this lesion (DNA hypermethylation) is commonplace in cancer, the results from these projects may have great relevance beyond GIST.