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，在美国将死于这种疾病的15,000多人年。占入侵性膀胱癌，占新诊断的膀胱癌的25％，通常会复发作为几乎没有有效治疗的致命转移性疾病。侵入性膀胱癌可能是分子归类为腔或更具侵略性的基本亚型，其具有高表达的表达 TP63并与其他碱性/鳞状肿瘤共享分子特征。我们已经确定了一种癌基因 - telangiectaisia d组D互补基因（ATDC，也称为 Trim29），通常在人类膀胱癌和驱动主动性和侵入性中表达转基因小鼠中膀胱肿瘤的进展。已知ATDC结合p53，调节DNA损伤反应，上调-catenin信号传导，促进了PTEN的沉默，并充当触发肿瘤的开关入侵。虽然ATDC是人膀胱癌中重要的致癌驱动器，但通常并不是突变的或放大和调查其表达的机制尚不清楚。我们发现ATDC表达标记了人类侵入性膀胱癌，这些癌症表现出基础表型，并且基底标记TP63，众所周知，这也促进了侵袭，似乎调节了ATDC的表达。因此，我们假设 TP63在膀胱癌（以及其他可能的其他肿瘤）中诱导了基本基因表达程序，需要促进肿瘤发生和侵入性进展的ATDC上调。更好表征TP63和ATDC在侵入性碱性膀胱癌中的作用，我们提出了以下研究：具体目标1：表征TP63 ATDC体外调节的机制。具体目标2：检查TP63和ATDC在侵入性进程中的作用。特定目标3：表征 ATDC对体内基本膀胱癌的发展的贡献。与其他恶性肿瘤相比，膀胱癌的研究较少，导致对驱动生物学，没有针对性的治疗方法。作为临床和研究的医学肿瘤学家关注膀胱癌患者，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我的患者的方法和新的预后生物标志物。这项工作具有创新性，因为我们将利用新型的转基因模型系统，人类样品，3D培养系统和下一代测序技术（BRU-SEQ，CHIP-SEQ）揭示了促进ATDC和TP63驱动事件的肿瘤癌症。该建议还将支持我作为一项基本/翻译研究的职业发展专注于膀胱癌，这是一个未满足的临床需求的领域。