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.

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.