# Epigenetic regulators of subtype plasticity in bladder cancer

> **NIH NIH F32** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $66,390

## Abstract

Project Summary/Abstract
 Bladder cancer can be subdivided into two categories: non-muscle invasive bladder cancer (NMIBC) and
muscle invasive bladder cancer (MIBC). NMIBC is treated by transurethral resection followed by either
intravesical immunotherapy or intravesical chemotherapy, which have a 10-year disease-specific survival of
75%. In contrast, standard of care for MIBC is radical cystectomy with either adjuvant or neoadjuvant
chemotherapy, with much lower disease-specific survival. However, approximately 20% of patients with high-
grade NMIBC will progress to MIBC, and ongoing studies have been unable to determine the molecular
mechanisms of this NMIBC-MIBC transition. Based on recent data from analyses of patient-derived bladder
tumor organoids, we propose that NMIBC that is prone to progress is epigenetically distinct from stable NMIBC
and transitions to MIBC through a mechanism of lineage plasticity. Specifically, a subset of organoids established
from luminal NMIBC tumors undergo a phenotypic switch in culture to a basal/squamous phenotype, which is
more typical of MIBC. Preliminary studies analyzing chromatin accessibility indicate that these phenotypically
plastic patient derived organoids (PDOs) are epigenetically distinct from phenotypically stable PDOs.
Furthermore, a chemical screen targeting epigenetic regulators in the phenotypically plastic organoid lines has
revealed a key pathway governing phenotypic plasticity.
 Based on the hypothesis that phenotypic plasticity and epigenetic regulators promote the transition of
NMIBC to MIBC, this proposed project will pursue two specific aims: (1) Map the chromatin accessibility and the
histone modification landscape of phenotypic plasticity in NMIBC and validate these findings in human patient
samples, and (2) Test whether the epigenetic regulators identified in a chemical screen can modulate plasticity
in bladder cancer and determine whether these regulators are potential novel therapeutic targets. Combined,
these two aims should lead to improved prediction of which high-grade NMIBCs will progress to MIBC and new
therapeutics for treatment of high-grade NMIBC.

## Key facts

- **NIH application ID:** 10235215
- **Project number:** 1F32CA261152-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** John Robert Christin
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235215

## Citation

> US National Institutes of Health, RePORTER application 10235215, Epigenetic regulators of subtype plasticity in bladder cancer (1F32CA261152-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10235215. Licensed CC0.

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