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

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.