FOXA1, GATA3 and PPARIγ Cooperate to drive luminal subtype in bladder cancer: A molecular analysis of established human cell lines

Joshua I. Warrick*, Vonn Walter, Hironobu Yamashita, Eunah Chung, Lauren Shuman, Vasty Osei Amponsa, Zongyu Zheng, Wilson Chan, Tiffany L. Whitcomb, Feng Yue, Tejaswi Iyyanki, Yuka I. Kawasawa, Matthew Kaag, Wansong Guo, Jay D. Raman, Joo Seop Park, David J. Degraff

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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 PPARI 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 PPARI drive luminal cell fate.

Original languageEnglish (US)
Article number38531
JournalScientific reports
Volume6
DOIs
StatePublished - Dec 7 2016

Funding

Supported by National Cancer Institute Grant R00CA172122 (D.J.D.), a Young Investigator Award from the Bladder Cancer Advocacy Network (D.J.D.), National Institutes DDK Grant DK100315 (J.-S.P.), the Ken and Bonnie Shockey Fund for Urologic Research (J.D.R), and a Herbert Brendler, MD Summer Medical Student Fellowship from the American Urological Association (W.C.).

ASJC Scopus subject areas

  • General

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