Meet the authors: Vasty Osei Amponsa and Kylie J. Walters.

We talk to Vasty Osei Amponsa and Kylie J. Walters about their paper "hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50", their journeys across continents leading them to the NCI, and how Kylie tries to foster curiosity and a sense of belonging in her lab.

Carcinogen-induced bladder cancer in the FVB mouse strain is associated with glandular differentiation and increased Cd274/Pdl-1 expression.

BACKGROUND: Creation of genetically engineered mouse models of bladder cancer often involves the use of several background strains in conjunction with the carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). However, carcinogen susceptibility in commonly used strains, as well as phenotypic differences is not well characterized. OBJECTIVES: To determine differences in susceptibility and phenotypic outcome following BBN exposure of C57BL/6 and FVB, two strains commonly used for model development. METHODS: Male C57BL/6 and FVB mice were exposed to BBN (0.05%) in drinking water for 12 and 16 weeks. Dissected bladders were characterized by histological and immunohistochemical analyses. Gene Ontology analysis was performed to identify differences in gene expression across strains following BBN exposure. RESULTS: While the C57BL/6 strain developed non-invasive tumors, FVB mice developed muscle invasive bladder cancer with squamous and/or glandular differentiation. Glandular differentiation was exclusively observed in the FVB strain. FVB tumors were highly immunogenic and inflamed by the presence of high expression of Cd274 (Pdl-1), murine histocompatibility complex (H2) and pro-inflammatory cytokines (Il-5 and Il-17). CONCLUSIONS: Following BBN exposure, FVB mice undergo rapid tumorigenesis and disease progression characterized by Pdl-1 expression and development of glandular differentiation. These studies identify a degree of tumor heterogeneity in the FVB tumors previously undescribed, and identify FVB mice as a potentially useful model for the study of bladder adenocarcinoma and the inflammatory tumor microenvironment.

On a FOX hunt: functions of FOX transcriptional regulators in bladder cancer.

Genomic and transcriptional studies have identified discrete molecular subtypes of bladder cancer. These observations could be the starting point to identify new treatments. Several members of the forkhead box (FOX) superfamily of transcription factors have been found to be differentially expressed in the different bladder cancer subtypes. In addition, the FOXA protein family are key regulators of embryonic bladder development and patterning. Both experimental and clinical data support a role for FOXA1 and FOXA2 in urothelial carcinoma. FOXA1 is expressed in embryonic and adult urothelium and its expression is altered in urothelial carcinomas and across disparate molecular bladder cancer subtypes. FOXA2 is normally absent from the adult urothelium, but developmental studies identified FOXA2 as a marker of a transient urothelial progenitor cell population during bladder development. Studies also implicate FOXA2 in bladder cancer and several other FOX proteins might be involved in development and/or progression of this disease; for example, FOXA1 and FOXO3A have been associated with clinical patient outcomes. Future studies should investigate to what extent and by which mechanisms FOX proteins might be directly involved in bladder cancer pathogenesis and treatment responses.

FOXA1, GATA3 and PPARÉ£ Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines.

Discrete bladder cancer molecular subtypes exhibit differential clinical aggressiveness and therapeutic response, which may have significant implications for identifying novel treatments for this common malignancy. However, research is hindered by the lack of suitable models to study each subtype. To address this limitation, we classified bladder cancer cell lines into molecular subtypes using publically available data in the Cancer Cell Line Encyclopedia (CCLE), guided by genomic characterization of bladder cancer by The Cancer Genome Atlas (TCGA). This identified a panel of bladder cancer cell lines which exhibit genetic alterations and gene expression patterns consistent with luminal and basal molecular subtypes of human disease. A subset of bladder cancer cell lines exhibit in vivo histomorphologic patterns consistent with luminal and basal subtypes, including papillary architecture and squamous differentiation. Using the molecular subtype assignments, and our own RNA-seq analysis, we found overexpression of GATA3 and FOXA1 cooperate with PPARÉ£ activation to drive transdifferentiation of a basal bladder cancer cells to a luminial phenotype. In summary, our analysis identified a set of human cell lines suitable for the study of molecular subtypes in bladder cancer, and furthermore indicates a cooperative regulatory network consisting of GATA3, FOXA1, and PPARÉ£ drive luminal cell fate.