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Project

Roles of epigenetic regulators in bladder cancer progression

Funder: University of California - Cancer Research Coordinating Committee

Funding period
USD 75 K
Funding amount
Abstract
Bladder cancer is one of the most costly cancers to treat; yet our understanding of cancer progression in the bladder is lagging behind other organs. One big obstacle in the field is the difficulty of building relevant bladder cancer mouse models, since the bladder urothelial cells are extremely resistant to transformation by just one or two oncogenes and no good bladder-specific Cre line is available. TCGA analyses of muscle invasive bladder cancer have revealed the top recurrent mutated genes, and inactivating mutations in three epigenetic regulators KMT2D, KDM6A, and ARID1A are very common. Based on this finding and previous in vitro studies in the field, we hypothesize that these three epigenetic regulators are essential for preventing bladder cancer progression. To test it, we have developed a novel method of delivering DNA plasmids into the mouse urothelium through electroporation, and built a baseline p53 Pten mouse bladder cancer model by delivering the CRISPR/Cas9 plasmids targeting those two genes. Our preliminary histology and sequencing data showed that this approach can reliably generate bladder tumors with advanced-stage carcinoma in situ, and that the resulting tumors can be clonally derived from individual mutant cells. We will therefore build gRNA plasmids targeting various combinations of the three chromatin-remodeling genes, and co-deliver them with the p53 Pten plasmid. We will perform histological analyses of the bladder tumors for different groups of mice at early and later time points, and determine whether further mutating any combinations of Kmt2d, Kdm6a, and Arid1a genes will promote bladder cancer progression. In sum, by developing and validating a novel CRISPR-based cancer modeling approach, my lab is well positioned to do complex genetic modeling of bladder cancer in vivo and study the molecular mechanisms. With the CRCC seed funding, this study has promise of revealing a driver’s role for key epigenetic regulators, and should lead to future NIH grant applications.
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System

Categories
  • FOR (ANZSRC)

    0604 Genetics

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science