Linking epigenetic regulation and TGF-β signaling in pancreatic cancer

项目总结/摘要 胰腺癌（PDAC）预计将成为美国癌症死亡的第二大原因， 到2020年，总体五年生存率<9%。早期转移是恶性肿瘤预后不良的主要原因之一。 生存最近的基因组测序研究比较了原发性肿瘤和转移性肿瘤， 存在突变，但未鉴定出特异性转移驱动因素。因此， 肿瘤进展--特别是转移--需要更多的研究。表观基因调控和 上皮向间质转化（EMT）是肿瘤进展的两种重要机制， 转移我们已经发现miR 455将转化生长因子-β（TGF-β）和EMT信号传导联系起来， 到组蛋白修饰。miR 455被TGF-β上调，这反过来又降低了KMT 2D的表达， KDM 6A，两种组蛋白修饰酶。我们的数据还显示，增加的miR 455或KDM 6A的丢失， 表达促进PDAC细胞EMT表型、迁移、侵袭、淋巴结转移和患者预后不良 生存在这个提议中，我们将定义miR 455介导的TGF-β信号转导和 表观遗传修饰在PDAC进展和转移中的作用我们的项目将揭示穷人- 了解PDAC进展和转移的表观遗传调控机制，这将进一步 有助于识别新的诊断和预后生物标志物和治疗靶点。 这个应用程序的总体目标是为我提供更多受保护的研究时间，获得初步数据， 发表在表观遗传学研究领域，并发展新的关键技能，使我成为一个R 01资助 表观遗传学和胰腺癌生物学的独立研究者。职业发展计划是基于 关于正式课程、讲习班、讲座、会议、体验式学习和指导基础科学 训练这个K 08奖励和额外的培训对我的职业发展至关重要，因为我的基本 我在临床培训期间的科学差距，该领域新知识和技术的发展，以及 我目前的临床职责我得到了我的部门的慷慨支持，并将与我的部门密切合作。 主要导师，博士Yali Dou，博士，表观遗传学专家，和共同导师博士Mats Ljungman，博士，a 转录调控和生物信息学的领导者，以及Marina Pasca di Magliano， 他是胰腺癌领域的专家，也是遗传小鼠模型生成和分析方面的专家。我也 成立了一个咨询委员会，以进一步支持我成为一名成功的内科医生和科学家。我会 我至少要把75%的时间用于基础科研研究。密歇根大学和 病理学在培养独立的癌症研究人员方面有着杰出的历史。统称 本提案的要素将为我提供成为一名 在表观遗传学和胰腺癌领域成功的独立医生-科学家。

Project Summary/Abstract Pancreatic adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the US by 2020 with an overall five-year survival rate of <9%. Early metastasis is one of the main reasons for poor survival. Recent genome sequencing studies comparing primary tumor and metastases determined that similar mutations are present, but no specific metastasis drivers were identified. Thus, mechanisms responsible for tumor progression—and specifically for metastasis—require more investigation. Epigenomic regulation and epithelial to mesenchymal transition (EMT) are two important mechanisms for tumor progression and metastasis. We have discovered that miR455 links Transforming Growth Factor-β (TGF-β) and EMT signaling to histone modification. miR455 is upregulated by TGF-β, which in turn reduces the expression of KMT2D and KDM6A, two histone modification enzymes. Our data also revealed that increased miR455 or loss of KDM6A expression promoted PDAC cell EMT phenotype, migration, invasion, lymph node metastasis, and poor patient survival. In this proposal, we will define miR455-mediated novel cross talk between the TGF-β signaling and epigenetic modification in PDAC progression and metastasis. Our project will shed light on the poorly- understood epigenetic regulatory mechanisms in PDAC progression and metastasis, which will further contribute to the identification of new diagnostic and prognostic biomarkers and therapeutic targets. The overall goal of this application is to provide me more protected research time, obtain preliminary data and publication in the epigenetic research field, and develop new critical skills for me to become an R01-funded independent investigator in epigenetics and pancreatic cancer biology. The career development plan is based on formal courses, workshops, lectures, conferences, experiential learning and mentored basic science training. This K08 award and additional training is critical to my career development because of the basic science gap during my clinical training, the development of new knowledge and technologies in the field, and my current clinical duties. I have received generous support from my department and will work closely with my primary mentor, Dr. Yali Dou, PhD, an expert in epigenetics, and co-mentors Drs. Mats Ljungman, PhD, a leader in transcriptional regulation and bioinformatics, and Marina Pasca di Magliano, a leader in the pancreatic cancer field and expert in the generation and analysis of genetic mouse models. I have also constructed an advisory committee to further support my development as a successful physician scientist. I will devote at least 75% of my time to basic scientific research. The University of Michigan and Department of Pathology has a distinguished history in the training of independent cancer researchers. Together, the elements of this proposal will provide me with the experience, training, and mentorship needed to become a successful independent physician-scientist in the field of epigenetics and pancreatic cancer.