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

项目摘要 BCCMA：退伍军人尿路上皮癌发生的基本和转化机制 暴露于致癌物：CMA 2：PPAR-T在乳腺癌形成和进展中的作用 膀胱原位 虽然膀胱癌（BC）在退伍军人中最常见的癌症中排名第四，但它具有 在基础、转化和临床方面， research.膀胱原位癌（CIS）是一种癌前病变，被认为是由特定的 烟草烟雾、职业和环境中的致癌物，复发率和进展率很高， 侵袭和转移。尽管其至关重要，但在基因组方面存在重大知识差距， CIS的表观遗传和转录基础，导致早期检测，准确 预测进展和预防。来自四个VA医疗中心的两名基础科学家和两名临床医生 已经联手解决CIS形成和发展的分子机制，在一个跨学科的 和协作的方式通过共享思想，试剂和资源。CMA 1将专注于机械 由EZH 2和多梳阻遏物复合物2（PRC 2）调节的人CIS的碱基。CMA 2旨在 了解转录控制，特别是PPAR-γ，从而CIS形成和发展到肌肉 入侵CMA 3将使用表观遗传方法，通过靶向赖氨酸- 特异性脱甲基酶1。CMA 4将开发生物标记驱动的人工智能增强膀胱镜 检测CIS和评估治疗反应的策略。广泛的串扰和相互作用已经投入 以提高整个计划的协同作用和效率。在一起，这种合作 该项目应该大大促进我们对CIS的遗传和表观遗传基础的理解， 新的诊断和治疗靶点，用于其敏感的检测、有效的治疗和早期预防。 理由：虽然我们显然需要更好地了解 尽管如此，在BC如何启动和进展方面，这方面的努力仍然严重不足。膀胱是一个容易接近的 怀疑有任何恶性潜力的病变理论上可以早期发现和监测 有效地一个典型的例子是CIS病变，这是一种膀胱粘膜衬里的癌前实体， 尽管不断监测和局部治疗，但仍经常复发并经常进展为肌肉浸润。 越来越多的证据表明，CIS是高度异质性的，表现出不同的生物学行为， 进步的风险。然而，不存在可靠的生物标志物来区分遗传或分子变异 在CIS。在本申请中，我们设计了一系列生理相关的体内实验， 检查控制正常膀胱上皮生长的特定转录因子的改变， 分化影响CIS形成和发展为肌层浸润性膀胱的不同亚型 癌我们还将评估生物学上不同的CIS病变如何具有不同的免疫状态， 可以探索信息以改善对局部免疫治疗剂的反应。 临床意义：我们希望我们提出的研究能够为分子基础提供新的见解。 潜在的CIS异质性和CIS病变与分子亚型之间的关系， 肌肉浸润性膀胱癌我们的研究应该产生生物学验证和机械基础 生物标志物集，可以潜在地用于临床早期CIS检测，风险分层和预测 进展我们的研究还应该确定新的分子，这些分子被证明对CIS的形成至关重要， 治疗靶向的进展。

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.