Investigating mechanisms of bladder tumorigenesis and therapeutic resistance

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Bladder cancer is the ninth most common malignancy globally, with over 600,000 new cases and 220,000 deaths reported in 2022. Despite recent therapeutic advances, treatment resistance remains a major challenge, contributing to persistently high mortality rates. The overarching goal of our laboratory is to elucidate the molecular mechanisms driving bladder tumorigenesis and therapeutic resistance. A key contributor to this resistance is tumor heterogeneity, which arises from diverse genetic landscapes shaped by distinct mutational processes during tumor evolution. We are particularly interested in understanding how the interplay between mutational processes and acquired genetic alterations leads to adaptive changes that confer survival advantages to cancer cells under selective pressures. Gaining insight into these adaptive and acquired mechanisms will enable the identification of therapeutically actionable pathways for treating bladder cancer. Aim 1: Mutational mechanisms driving tumor evolution and heterogeneity. Our current focus is on APOBEC3-mediated mutagenesis, a predominant and ongoing mutational process in bladder cancer. We are employing integrative multi-omics and functional approaches to: a) Identify both intrinsic and extrinsic factors that promote or inhibit APOBEC-mediated mutagenesis; b) Investigate the role of APOBEC enzymes in driving tumor evolution, intratumoral heterogeneity, and therapeutic resistance or response; c) Evaluate the druggability of APOBEC enzymes as potential therapeutic targets. Aim 2: Molecular and phenotypic characterization of recurrent genomic alterations Tumor genomes harbor a wide array of alterations, the functional and therapeutic consequences of which remain poorly characterized-beyond a limited set of well-established oncogenes and tumor suppressors. Recent advances in functional genomics have enabled high-throughput evaluation of these alterations at scale. Using bladder cancer as a model, we are systematically studying recurrent somatic alterations-both genomic and transcriptomic-through high-throughput platforms, including CRISPR-mediated gene editing, activation, and interference for massively parallel perturbation in vitro and in vivo. Our goal is to determine how these alterations contribute to malignant transformation, tumor subtype specification, epithelial-to-mesenchymal transition (EMT), metastasis, modulation of the tumor immune microenvironment, and response to therapy. We have identified several recurrent non-coding mutations and novel oncogenes that drive bladder cancer, as well as recurrent copy number gains involving oncogenes and genes that promote an immune-cold tumor phenotype and reduce the efficacy of immunotherapy drugs.