title: FOXA1, GATA3 and PPARɣ Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines.
abstract: 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 PPARɣ 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 PPARɣ drive luminal cell fate.
authors.affiliation: Department of Pathology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA.|Department of Surgery, Division of Urology, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Warrick
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, PA, USA.|Department of Public Health Sciences, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Vonn
authors.initials: V
authors.lastname: Walter
authors.affiliation: Department of Pathology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Division of Pediatric Urology and Developmental Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
authors.forename: Eunah
authors.initials: E
authors.lastname: Chung
authors.affiliation: Department of Pathology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA.|Department of Surgery, Division of Urology, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Shuman
authors.affiliation: Department of Pathology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Vasty Osei
authors.initials: VO
authors.lastname: Amponsa
authors.affiliation: Department of Pathology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Zongyu
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA.|Department of Surgery, Division of Urology, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Chan
authors.affiliation: Department of Comparative Medicine, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Whitcomb
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, PA, USA.|Institute for Personalized Medicine, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Tejaswi
authors.initials: T
authors.lastname: Iyyanki
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, PA, USA.|Institute for Personalized Medicine, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Yuka I
authors.initials: YI
authors.lastname: Kawasawa
authors.affiliation: Department of Surgery, Division of Urology, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kaag
authors.affiliation: Department of Surgery, Division of Urology, Changchun Central Hospital, Changchun, China.
authors.forename: Wansong
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Raman
authors.affiliation: Division of Pediatric Urology and Developmental Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
authors.forename: Joo-Seop
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Pathology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA.|Department of Surgery, Division of Urology, Pennsylvania State University College of Medicine, PA, USA.|Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: DeGraff
mesh_terms: D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D017423:Sequence Analysis, RNA; D001749:Urinary Bladder Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C496499:FOXA1 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D047495:PPAR gamma