TERT transcriptional deregulation in thyroid cancer progression

甲状腺癌进展中的 TERT 转录失调

基本信息

批准号：
10401447
负责人：
Inigo Landa-Lopez
金额：
$ 19.55万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-13 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401447
关键词：
Advisory Committees Alleles Apoptosis BRAF gene Behavior Binding Biological Biological Markers Biology Cancer Biology Cancer Model Cause of Death Cell Aging Cell Lineage Cell Survival Cell division Cells Chromatin Chromosomes Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Consensus Data Development Devices Disease Enhancers Enzymes Event Family Family member Genes Genetic Genetic Transcription Genetically Engineered Mouse Genome Genomics Glioblastoma Goals Grant Human K22 Award Knock-in Longevity MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of thyroid Mediating Modeling Molecular Target Mus Mutation Neoplasm Metastasis Normal Cell Oncogenic Oncoproteins Papillary thyroid carcinoma Patients Phenotype Positioning Attribute Predisposition Prognosis Promoter Regions RNA-Directed DNA Polymerase Radiation therapy Refractory Regulation Reporting Research Research Personnel Resources Role Secure Severity of illness Signal Pathway Signal Transduction Tandem Repeat Sequences Telomerase Telomere Shortening Testing The Cancer Genome Atlas Therapeutic Thyroid Gland Time Training Transcriptional Regulation Variant anaplastic thyroid cancer cancer cell cancer genetics cancer genomics career chemotherapy clinically significant experimental study gene repression in vivo melanoma mouse model mutant mutant mouse model novel overexpression preclinical study prevent promoter radioiodine therapy telomere tenure track thyroid neoplasm tool transcription factor transcriptomics tumor tumor progression tumorigenesis virtual

项目摘要

PROJECT SUMMARY / ABSTRACT TERT transcriptional deregulation in thyroid cancer progression I trained in thyroid cancer genetics in my graduate studies, during which time I identified germline promoter variants conferring thyroid cancer susceptibility. In my postdoctoral years I led a project that revealed the key somatic genomic and transcriptomic hallmarks of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers. We reported that mutations in the promoter of TERT (telomerase reverse transcriptase) gene are the most prevalent genetic alterations in often fatal PDTCs and ATCs, and constitute good biomarkers of disease severity. Although it is widely accepted that TERT promoter mutations activate gene transcription, the specific mechanisms and biological effects of these alterations remain largely unknown. This prompted me to study the role of TERT transcriptional deregulation in thyroid cancer progression, which is the subject of my K22 proposal. I believe this project has great potential and will facilitate my setting up my own lab. To this end, I have put together an advisory committee and collaborators who will share their expertise and resources in the fields of transcriptional regulation, chromatin biology and genetically engineered mouse models of cancer, as well as career advice, while I seek to secure a tenure-track position. This proposal outlines a comprehensive approach to characterizing the role of TERT promoter mutations in telomerase transcriptional deregulation and thyroid cancer progression. The first aim of this project is to identify the transcriptional complex that differentially binds TERT mutant vs. wildtype promoter, and to this end I propose a dual regulation model. First, we describe experiments to define the role of specific ETS family members in TERT mutant promoter reactivation, which we believe are distinct from those reported in other disease contexts. We will also evaluate the effect of MAPK constitutive signaling, a hallmark of thyroid tumors, in ETS-mediated TERT expression. Second, we aim to unveil the influence of the CTCF genome insulator on TERT transcriptional repression through long-range enhancer- promoter interactions. We have preliminary data suggesting that ETS and CTCF factors compete for TERT promoter binding in mutant and wildtype conditions, respectively, inducing opposite effects on gene transcription. Our second aim is to characterize the first Tert mutant promoter mouse model, which we have already generated via CRISPR knock-in of the equivalent mouse locus. Our preliminary data suggest that Tert promotes thyroid cancer progression in combination with a thyroid-specific oncogenic BrafV600E allele. We will also assess which signaling pathways are involved in Tert-induced thyroid tumors, and whether they create unique vulnerabilities that can be exploited therapeutically. Overall, my goal is to establish myself as an independent investigator in the field of thyroid cancer biology and transcriptional regulation, and the awarding of the K22 grant will greatly facilitate this transition.

项目概要/摘要甲状腺癌进展中的 TERT 转录失调我在研究生学习期间接受了甲状腺癌遗传学培训，在此期间我发现了种系启动子变异赋予甲状腺癌易感性。在我的博士后岁月里，我领导了一个项目，揭示了关键低分化（PDTC）和未分化（ATC）甲状腺的体细胞基因组和转录组特征癌症。我们报道了TERT（端粒酶逆转录酶）基因启动子的突变致命的 PDTC 和 ATC 中最常见的基因改变，构成良好的疾病生物标志物严重程度。尽管人们普遍认为 TERT 启动子突变会激活基因转录，但具体的这些改变的机制和生物学效应仍然很大程度上未知。这促使我研究 TERT 转录失调在甲状腺癌进展中的作用，这是我的 K22 提案的主题。我相信这个项目具有巨大的潜力，并将有助于我建立自己的实验室。为此，我把咨询委员会和合作者将共同分享他们在以下领域的专业知识和资源：转录调控、染色质生物学和基因工程小鼠癌症模型，以及职业建议，同时我寻求获得终身教职。该提案概述了一个全面的方法表征 TERT 启动子突变在端粒酶转录失调和甲状腺中的作用癌症进展。该项目的第一个目标是识别差异结合的转录复合物 TERT突变体与野生型启动子，为此我提出了双重调控模型。首先，我们描述确定特定 ETS 家族成员在 TERT 突变启动子重新激活中的作用的实验，我们相信与其他疾病背景中报道的不同。我们还将评估MAPK的效果 ETS 介导的 TERT 表达中的组成型信号传导是甲状腺肿瘤的标志。其次，我们的目标是揭开 CTCF基因组绝缘子通过长程增强子对TERT转录抑制的影响- 启动子相互作用。我们有初步数据表明 ETS 和 CTCF 因素竞争 TERT 启动子分别在突变型和野生型条件下结合，对基因转录产生相反的影响。我们的第二个目标是表征第一个 Tert 突变启动子小鼠模型，我们已经生成了该模型通过 CRISPR 敲入等效的小鼠基因座。我们的初步数据表明 Tert 促进甲状腺与甲状腺特异性致癌 BrafV600E 等位基因相结合的癌症进展。我们还将评估哪些信号通路参与 Tert 诱导的甲状腺肿瘤，以及它们是否会产生独特的脆弱性可以用于治疗。总的来说，我的目标是让自己成为一名独立调查员 K22基金的授予将极大地促进甲状腺癌生物学和转录调控领域的发展促进这一转变。