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Project

Epigenetic regulators of subtype plasticity in bladder cancer

Funder: Bladder Cancer Advocacy Network

Funding period
USD 2 K
Funding amount
Abstract
BackgroundBladder cancer can be divided into two subtypes based on gene expression: basal and luminal. Importantly, these subtypes are clinically relevant as patients with basal tumors have worse overall survival than patients with luminal tumors. Previously, intrinsic subtypes were thought to be invariant for each tumor. However, we have observed that tumor subtype can be plastic, in studies of patient-derived organoids (PDOs). Hypothesis and Specific AimsI hypothesize that phenotypic plasticity in bladder cancer can be understood by investigating the regulation of the epigenome. I will test this hypothesis in two ways. (1) I will characterize the epigenetic landscape of bladder cancer during the transition from luminal to basal state using the Assay for Transposase-Accessible Chromatin (ATAC)-Seq. This will be used to create an epigenetic signature that can predict phenotypic plasticity or stability. I will validate this signature using fresh patient samples, followed by analysis of archival samples from patients with known outcomes to determine whether phenotypic plasticity is associated with clinical outcomes such as the transition from non-muscle invasive bladder cancer (NMIBC) to muscle invasive bladder cancer (MIBC). (2) I will screen organoids in vitro with a library of chemical probes that inhibit epigenetic regulators. After the identification of compounds capable of reversing the luminal to basal transition, I will use ATAC-Seq to profile the chromatin landscape. I will then pursue a candidate-based approach to identify which epigenetic regulators regulate luminal-basal identity and validate them in vivo.Patient ImpactThrough this research, I will advance translational bladder cancer research by showing how bladder cancer plasticity is regulated. With this knowledge, it may be possible to predict the transition from NMIBC to MIBC. It may also allow for the development of novel therapies targeting epigenetic regulators to prevent this transition.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Human Genome

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • 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