BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Role of PPARg in theFormation and Progression of Carcinoma in situ of the Bladder

BCCMA：暴露于致癌物的退伍军人尿路上皮癌症发生的基本和转化机制：PPARg 在膀胱原位癌形成和进展中的作用

• 批准号: 10361590
• 负责人: XUE-RU WU
• 金额: --
• 依托单位: VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361590
• 关键词: Affect; Animal Model; Area; Artificial Intelligence; Attention; Automobile Driving; Basic Science; Behavior; Biological; Biological Markers; Bladder; Bladder mucosa; CDH1 gene; Carcinogens; Carcinoma in Situ; Cells; Clinical; Clinical Research; Cytogenetic Analysis; Data; Detection; Diagnosis; Differentiation Antigens; Differentiation and Growth; Dominant-Negative Mutation; Doxycycline; EZH2 gene; Early Diagnosis; Emotional; Environment; Epigenetic Process; Epithelial; Exhibits; Exposure to; GTP-Binding Protein alpha Subunits, Gs; Genetic; Genetic Drift; Genetic Transcription; Genetically Engineered Mouse; Genomics; Heterogeneity; Human; Immune; Immunotherapeutic agent; Immunotherapy; In Situ Lesion; Infiltration; KDM1A gene; Knock-out; Knowledge; Lesion; Local Therapy; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical; Medical center; Modeling; Molecular; Monitor; Muscle; Neoplasm Metastasis; Occupations; Oncogenic; Organ; PPAR gamma; Pain; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Polycomb; Prevention; Quality of life; Radical Cystectomy; Radio; Reagent; Recurrence; Repressor Proteins; Research Proposals; Resources; Risk; Role; Scientist; Series; Smoking; Squamous cell carcinoma; System; TP53 gene; Tamoxifen; Testing; Tobacco smoke; Transcriptional Regulation; Translational Research; Treatment Efficacy; Tumor-infiltrating immune cells; UPK2 gene; Urothelial Cell; Urothelium; Variant; Veterans; base; biomarker-driven; bladder carcinoma in situ; cancer initiation; chemical carcinogenesis; cost; design; effective therapy; experience; experimental study; genetic analysis; immunological status; improved; in vivo; insight; intravesical; lost work time; molecular subtypes; muscle invasive bladder cancer; mutant; new therapeutic target; novel; novel diagnostics; premalignant; prevent; programs; response; risk prediction; risk stratification; single-cell RNA sequencing; synergism; therapeutic target; transcription factor; treatment response

Project Summary Abstract BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: CMA2: Role of PPAR- in the Formation and Progression of Carcinoma in situ of the Bladder Although bladder cancer (BC) ranks the fourth among the most prevalent cancers in the Veterans, it has received a level of attention far less than many other prevalent cancers in basic, translational and clinical research. Carcinoma in situ (CIS) of the bladder is a precancerous lesion, believed to be caused by specific carcinogens in tobacco smoke, occupation and environment, has a high rate of recurrence and progression to invasion and metastasis. Despite its critical importance, major knowledge gaps exist regarding the genomic, epigenetic and transcriptional underpinning of CIS, leading to unmet challenges in early detection, accurate prediction of progression and prevention. Two basic scientists and two clinicians from four VA Medical Centers have joined forces to tackle the molecular mechanisms of CIS formation and progression in an interdisciplinary and collaborative manner by sharing ideas, reagents and resources. CMA1 will focus on the mechanistic bases of human CIS regulated by EZH2 and the polycomb repressor complex 2 (PRC2). CMA2 aims to understand the transcriptional controls, especially PPAR-γ, whereby CIS forms and progresses to muscle invasion. CMA3 will use epigenetic approaches to prevent or delay smoking-related BC by targeting lysine- specific demethylase 1. CMA4 will develop a biomarker-driven, artificial intelligence-enhanced cystoscopic strategy to detect CIS and assess treatment response. Extensive crosstalk and interactions have been put in place in each CMA to enhance the synergy and efficiency of the entire program. Together, this collaborative project should significantly advance our understanding of the genetic and epigenetic bases of CIS, yielding novel diagnostic and therapeutic targets for its sensitive detection, effective treatment and early prevention. Rationale: While there is a clear need for us to better understand the fundamental mechanisms underlying how BC initiates and progresses, efforts in this area remain grossly inadequate. Bladder is an easily accessible organ, and lesions suspected of any malignant potential can theoretically be detected early and monitored effectively. A typical example is the CIS lesion, a precancerous entity of the bladder mucosa lining that is highly recurrent and frequently advances to muscle invasion despite constant surveillance and local therapies. Accumulating evidence suggests that CIS is highly heterogeneous, exhibiting diverse biological behaviors and risks of progression. However, no reliable biomarkers exist to differentiate the genetic or molecular variants within CIS. In this application, we have devised a series of physiologically relevant, in vivo experiments to examine whether alternations in specific transcription factors that control normal bladder epithelial growth and differentiation affect the formation and progression of CIS into different subtypes of muscle-invasive bladder cancer. We will also assess how biologically different CIS lesions have differed immune status and how that information can be explored to improve responses to local immunotherapeutics. Clinical implications: We expect our proposed studies to offer new insights into the molecular bases underlying the heterogeneity of CIS and the relationship between CIS lesions and the molecular subtypes of muscle-invasive bladder cancer. Our studies should yield biologically validated and mechanistically based biomarker sets that can potentially be used clinically for early CIS detection, risk stratification and prediction of progression. Our studies should also identify new molecules that are proven critical for CIS formation and progression for therapeutic targeting.

项目摘要摘要 BCCMA：退伍军人尿路上皮的癌症启动的基本和翻译机制 暴露于致癌物：CMA2：PPAR-在癌中的形成和进展中的作用 膀胱 尽管膀胱癌（BC）在退伍军人中最普遍的癌症中排名第四，但它具有 在基本，翻译和临床上，受到的关注程度远低于许多其他普遍的癌症 研究。膀胱的原位癌是癌性病变，被认为是由特定的 烟草烟雾，占领和环境中的致癌物具有很高的复发率和进展。 入侵和转移。尽管其重要性至关重要，但存在有关基因组的主要知识差距， 顺式的表观遗传和转录基础，导致早期检测中未满足的挑战，准确 预测进展和预防。来自四个VA医疗中心的两名基本科学家和两个临床医生 已经联合解决了跨学科中顺式形成和进展的分子机制 通过分享思想，试剂和资源来协作方式。 CMA1将重点放在机械上 由EZH2和Polycomb复制器复合物2（PRC2）调节的人类CI的碱基。 CMA2的目的是 了解转录控件，尤其是PPAR-γ，从而形成并发展为肌肉 入侵。 CMA3将使用表观遗传方法来通过靶向赖氨酸来预防或延迟吸烟相关的BC 特定的脱甲基酶1。CMA4将开发一个生物标志物驱动的人工智能增强的膀胱镜 检测CI和评估治疗反应的策略。广泛的串扰和互动已被提出 放入每个CMA，以增强整个程序的协同作用和效率。在一起，这个合作 项目应大大提高我们对CI的遗传和表观遗传基础的理解，从而产生 新颖的诊断和治疗靶标，用于其敏感检测，有效的治疗和早期预防。 基本原理：虽然我们显然需要更好地了解基本机制 卑诗省如何发起和进步，在这一领域的努力仍然非常不足。膀胱很容易进入 可以提早检测到器官和怀疑具有任何恶性潜力的病变 一个典型的例子是顺式病变，这是膀胱粘膜衬里的癌前实体 肌肉入侵目的地的经常性并经常进步持续监测和局部疗法。 积累的证据表明，CI是高度异质的，表现出潜水员的生物学行为和 进展的风险。但是，没有可靠的生物标志物来区分遗传或分子变异 在顺式内。在此应用中，我们设计了一系列与身体相关的体内实验 检查控制正常膀胱上皮生长和 分化会影响顺式肌肉侵入性膀胱的不同亚型的形成和发展 癌症。我们还将评估生物学上不同的顺式病变如何具有不同的免疫状态以及如何 可以探索信息以改善对局部免疫治疗剂的反应。 临床意义：我们预计我们提出的研究将为分子碱提供新的见解 基础，顺式的异质性以及顺式病变与分子亚型之间的关系 肌肉侵入性膀胱癌。我们的研究应产生经过生物学验证的机械验证的 生物标志物套件可能在临床上用于早期CIS检测，风险分层和预测 进展。我们的研究还应确定被证明对CIS形成至关重要的新分子 治疗靶向的进展。