TCF21 promotes luminal-like differentiation and suppresses metastasis in bladder cancer

Little is known regarding the subclone evolution process in advanced bladder cancer (BLCA), particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic BLCA through mRNA expression profiling of RNA isolated from 33 primary BLCA and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary BLCA compared to LN metastasis samples. To elucidate its function in BLCA, loss- and gain-of-function experiments were conducted in BLCA cell lines with high and low expression of TCF21, respectively. We also performed GEP in BLCA cell lines following TCF21 overexpression. We identified 2390 genes differentially expressed in primary BLCA and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared to LN metastasis. We validated this finding with Q-PCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal BLCA cell lines decreased their invasive and metastatic potential. Implications: TCF21 is differentially overexpressed in primary BLCA compared to matched LN metastasis, with in vitro and in vivo studies demonstrating a metastasis suppressor function of this transcription factor.