Project 1: Understanding the Evolution of Bladder Cancer from Field Effects

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Abstract

Project 1 – Summary Bladder cancer is a common human malignancy related to tobacco smoking and exposure to chemical, industrial, or environmental carcinogens. It develops from precursor lesions in the urothelial layer of the bladder along two distinct tracts referred to as papillary and nonpapillary that represent clinically and molecularly different forms of the disease. In this grant application, we propose to perform whole-organ, multiplatform genomic studies of molecular profiles of bladder cancer development from early mucosal field effects through in situ preneoplastic conditions to clinically evident aggressive disease. These studies will be complemented by in-depth characterization of molecular mechanisms regulated by the forerunner (FR) genes lysophosphatidic acid receptor 6 (LPAR6) and calcium-binding protein 39-like (CAB39L), which control urothelial differentiation. Our preliminary data demonstrated that loss of their function, predominantly due to hypermethylation, dysregulates basal to luminal urotheilal differentiation program. We hypothesized that early changes in microscopically normal mucosa, referred to as field effects, dysregulate urothelial differentiation and contribute to bladder cancer development. We will test this hypothesis in three specific aims: 1) characterize the evolution of the genomic profile of bladder cancer from initiating field effects, 2) identify the biologic effects and molecular pathways controlled by FR genes, and 3) identify the involvement of FR genes in molecular subtypes of bladder cancer. When completed, this project will provide a detailed chronologic atlas of bladder cancer evolution from mucosal field effects complemented by in-depth characterization of signature molecular mechanisms initiating bladder carcinogenesis. Collaborative studies between Projects 1 and 2 will focus on the role of luminal dysregulation controlled by nuclear receptors such as PPARG in the evolution of bladder cancer from mucosal field effects and in bladder cancer cell lines as well as animal models exploring the role of phenotypic luminal to basal plasticity in therapeutic response. Similarly, collaborative studies between Projects 1 and 3 will investigate the expression pattern of IFN target genes in the evolution of bladder cancer from mucosal field effects as well as the role of luminal to basal plasticity in therapeutic response. The data generated by this project will facilitate early bladder cancer detection and bladder cancer prevention and will identify novel targets for therapeutic interventions. The Pathology Core will provide tissue and analytical assistance for all aims. The Biostatistics and Bioinformatics Core will analyze the data for all aims. The Administrative Core will assist with strategic oversight, regulatory issues, and communication with other projects and cores and the funding agency.