Abstract A28: Deregulation of KMT2D promotes squamous differentiation in a mouse model of muscle-invasive bladder cancer

Abstract

Abstract Cell differentiation and plasticity is precisely controlled by specific gene expression programs coordinate with chromatin remodeling, which are often deregulated during tumorigenesis. While divergent histopathologic differentiation in bladder cancer is prevalent and may affect clinical outcome, the underlying mechanisms are not well understood. Here, we aim to elucidate mechanisms for alteration of the histopathologic and molecular features of muscle-invasive bladder cancer (MIBC) by interrogating the functional role of chromatin-remodeling genes using relevant genetically engineered mouse models (GEMMs). High frequency of mutations in chromatin-remodeling genes encoding COMPASS-like chromatin-remodeling complex members has been identified in human MIBC. These genes include “writers” that create histone post-translational modification, such as the lysine methyltransferase KMT2D (MLL2/4), and “erasers” that remove these modifications, such as the lysine demethylase KDM6A (UTX). We have generated GEMMs that enable bladder-specific conditional inactivation of individual chromatin-remodeling genes in combination with loss of function of Trp53 and Pten, which leads to MIBC. Interestingly, bladder tumors from GEMMs having inactivation of Kmt2d along with Trp53 and Pten (e.g., Kmt2d;Trp53;Pten mice) develop a variant histologic phenotype that is not observed in tumors from either the Trp53;Pten or Kdm6a;Trp53;Pten mice. Specifically, these Kmt2d-inactivated tumors share histopathologic features in common with human urothelial carcinoma that display squamous differentiation. Furthermore, expression profiling of these Kmt2d;Trp53;Pten bladder tumors identified a unique set of differentially expressed genes that are enriched for genes representing squamous differentiation in other nonbladder cancers. Our findings suggest that deregulated Kmt2d expression promotes squamous differentiation in MIBC, at least in context of Trp53;pten coinactivation. Citation Format: Lijie Rong, Cory Abate-Shen. Deregulation of KMT2D promotes squamous differentiation in a mouse model of muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A28.