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.

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

“…lncRNA subtypes 2 and 3 (Figure 4A) were both associated with the luminal-papillary mRNA subtype and showed similar activation profiles for 9 regulons. Their profiles were consistent with the hypothesis that transcription factors GATA3 , FOXA1 , and PPARɣ drive luminal cell biology in bladder cancer (Warrick et al, 2016). The better-survival lncRNA 3 differed from lncRNA 2 by having, among other characteristics, an activated regulon for FGFR3 and undefined (i.e.…”

Molecular pathology of the luminal class of urothelial tumors

“…All tumors subtypes, with the possible exception of UroB, expressed PPARG and GATA3, indicating that parts of the normal differentiation pathway are present . Consequently, the expression of the differentiation markers KRT20 and UPK3 in a subpopulation of tumors may not come as a surprise.…”

Genomic Activation of PPARG Reveals a Candidate Therapeutic Axis in Bladder Cancer

“…PPARG agonists upregulate expression of luminal differentiation markers UPK1A, UPK1B, and KRT20 in primary rat urothelial cells (49). These same genes, plus GATA3, and FOXA1 are the key luminal markers of bladder cancer from human patients (13,14) and bladder cancer cell lines (16). The lineage-defining role of GATA3, FOXA1, and PPARG in luminal bladder cancer is reminiscent of luminal breast cancer, in which coordinated expression of GATA3, FOXA1, and ESR1 enable chromatin remodeling and regulate luminal gene expression programs (50,51).…”

“…1B) as well as expression of PPARG target genes and luminal differentiation markers such as GATA3, UPK2, ACOX1 , and UPK1A (Supplementary Fig. 1C and (13–16)). PPARG is a master regulator of adipocyte differentiation and controls expression of a large set of genes involved in lipid and glucose homeostasis (12).…”