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Regulation of ATDC by TP63 and its role in bladder cancer

TP63对ATDC的调控及其在膀胱癌中的作用

基本信息

批准号：
9763474
负责人：
PHILLIP L PALMBOS
金额：
$ 17.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763474
关键词：
3-Dimensional Address Area Ataxia-Telangiectasia Group D Complementing Automobile Driving Basal Cell Binding Biological Assay Biological Markers Biological Models Biology Bladder Neoplasm Bromouridine sequencing Cancer cell line Cells Cellular biology Cessation of life ChIP-seq Clinical Clinical Research DNA Damage Data Development Diagnosis Disease Epithelial Event Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Growth Human In Vitro Investigation Knockout Mice Knowledge Lead Malignant Neoplasms Malignant neoplasm of urinary bladder Medical Oncologist Mentors Molecular Mus Mutate Newly Diagnosed Oncogenes Oncogenic Organoids Outcome PTEN gene Patients Performance Phenotype Prognostic Marker Regulation Research Research Personnel Role Sampling Signal Transduction System TP53 gene Technology Therapeutic Time Tissues Training Transgenic Mice Transgenic Model Translational Research Tumor Cell Invasion United States Up-Regulation Urothelial Cell Work cancer cell career development chemical carcinogen effective therapy experience gene complementation improved in vitro Model in vivo innovation knock-down mRNA Expression mortality mouse model next generation sequencing novel novel therapeutics outcome forecast overexpression programs protein expression response targeted biomarker targeted treatment therapeutic target three dimensional cell culture transcriptome sequencing tumor tumor progression tumorigenesis

项目摘要

Abstract Bladder cancer is a common and deadly disease and over 15,000 people will die of this disease in the US this year. Invasive bladder cancers, which account for 25% of newly-diagnosed bladder cancers, commonly recur as lethal metastatic disease for which few effective treatments exist. Invasive bladder cancers can be molecularly classified as either luminal or the more aggressive basal subtypes which have high expression of TP63 and share molecular features with other basal/squamous tumors. We have identified an oncogene, Ataxia-Telangiectasia Group D Complementing gene (ATDC, also known as TRIM29), which is commonly expressed in human bladder cancers and drives initiation and invasive progression of bladder tumors in transgenic mice. ATDC is known to bind p53, modulate DNA damage responses, up-regulates -catenin signaling, promotes silencing of PTEN and acts as a switch triggering tumor invasion. While ATDC is an important oncogenic driver in human bladder cancers, it is not commonly mutated or amplified and the mechanism(s) regulating its expression are unknown. We find that ATDC expression marks human invasive bladder cancers which display a basal phenotype and that the basal marker, TP63, which is also known to promote invasion, appears to regulate expression of ATDC. We therefore hypothesize that TP63 induces a basal gene expression program in bladder cancer (and likely other tumors as well), requiring upregulation of ATDC which promotes tumorigenesis and invasive progression. To better characterize the role of TP63 and ATDC in invasive basal bladder cancer, we propose the following studies: SPECIFIC AIM 1: To characterize the mechanism(s) of TP63 regulation of ATDC in vitro. SPECIFIC AIM 2: To examine the role of TP63 and ATDC in invasive progression. SPECIFIC AIM 3: To characterize the contribution of ATDC to development of basal bladder cancers in vivo. Compared to other malignancies, bladder cancer is less studied resulting in a limited understanding of the driving biology and no targeted therapeutic approaches. As a medical oncologist with a clinical and research focus on patients with bladder cancer, I believe the studies proposed here are significant because understanding ATDC and TP63’s oncogenic activity in bladder cancer may lead to improved therapeutic approaches and new prognostic biomarkers for my patients. This work is innovative because we will utilize novel transgenic model systems, human samples, 3D culture systems, and next generation sequencing technology (Bru-seq, ChIP-seq) to uncover the tumor promoting events driven by ATDC and TP63 in bladder cancer. This proposal will also support my career development as a basic/translational research with specific focus on bladder cancer, an area of unmet clinical need.

抽象的膀胱癌是一种常见且致命的疾病，今年美国将有超过 15,000 人死于这种疾病。年。侵袭性膀胱癌占新诊断膀胱癌的 25%，通常会复发作为致命的转移性疾病，几乎没有有效的治疗方法。侵袭性膀胱癌可能是分子上分为管腔亚型或更具攻击性的基础亚型，这些亚型具有高表达 TP63 与其他基底/鳞状肿瘤具有相同的分子特征。我们已经鉴定出一种癌基因，共济失调毛细血管扩张 D 组互补基因（ATDC，也称为 TRIM29），通常在人类膀胱癌中表达并驱动起始和侵袭性转基因小鼠膀胱肿瘤的进展。 ATDC 已知可结合 p53，调节 DNA 损伤反应，上调 -连环蛋白信号传导，促进 PTEN 沉默并充当触发肿瘤的开关入侵。虽然 ATDC 是人类膀胱癌的重要致癌驱动因素，但它并不常见突变或扩增，调节其表达的机制尚不清楚。我们发现 ATDC 表达式标记显示基础表型的人类浸润性膀胱癌，并且基础标记 TP63 它也被认为可以促进侵袭，似乎可以调节 ATDC 的表达。因此我们假设 TP63 在膀胱癌（也可能还有其他肿瘤）中诱导基础基因表达程序，需要上调 ATDC，从而促进肿瘤发生和侵袭进展。为了更好为了表征 TP63 和 ATDC 在浸润性基底膀胱癌中的作用，我们提出以下研究：具体目标 1：表征 TP63 在体外调节 ATDC 的机制。具体目标 2：研究 TP63 和 ATDC 在侵袭性进展中的作用。具体目标 3：表征 ATDC 对体内基底膀胱癌发展的贡献。与其他恶性肿瘤相比，膀胱癌的研究较少，导致人们对膀胱癌的了解有限。驱动生物学并且没有针对性的治疗方法。作为一名具有临床和研究经验的肿瘤内科医生重点关注膀胱癌患者，我相信这里提出的研究很重要，因为了解 ATDC 和 TP63 在膀胱癌中的致癌活性可能会改善治疗为我的患者提供新的预后生物标志物。这项工作是创新的，因为我们将利用新型转基因模型系统、人类样本、3D 培养系统和下一代测序技术（Bru-seq、ChIP-seq）揭示膀胱中 ATDC 和 TP63 驱动的肿瘤促进事件癌症。该提案还将支持我作为具有特定基础/转化研究的职业发展重点关注膀胱癌，这是一个临床需求未得到满足的领域。