PD37-02 FOXF1 IS A NOVEL REGULATOR OF NODAL METASTASIS IN BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (PD37)1 Sep 2021PD37-02 FOXF1 IS A NOVEL REGULATOR OF NODAL METASTASIS IN BLADDER CANCER Anirban P. Mitra, Andrea Kokorovic, Tanner S. Miest, Vikram M. Narayan, Debasish Sundi, Amy Lim, Sharada Mokkapati, and Colin P. N. Dinney Anirban P. MitraAnirban P. Mitra More articles by this author , Andrea KokorovicAndrea Kokorovic More articles by this author , Tanner S. MiestTanner S. Miest More articles by this author , Vikram M. NarayanVikram M. Narayan More articles by this author , Debasish SundiDebasish Sundi More articles by this author , Amy LimAmy Lim More articles by this author , Sharada MokkapatiSharada Mokkapati More articles by this author , and Colin P. N. DinneyColin P. N. Dinney More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002047.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Members of the forkhead transcription factor (FOX) family mediate embryonic development and are altered in many cancers. The functional role of FOXF1 in bladder cancer progression is unclear thus far. We investigated the clinical implications of differential FOXF1 expression in bladder cancer and potential mechanisms by which its alteration can lead to metastasis. METHODS: Whole genome expression profiling performed on paired primary tumors and nodal metastases from a radical cystectomy discovery cohort using Illumina HT12 v3-4 BeadChip arrays identified FOXF1 as a top differentially expressed gene. Prognostic role of differential FOXF1 expression was validated in two independent cystectomy cohorts. Differential FOXF1 expression was also evaluated in murine orthotopic xenografts. Small interfering RNA was used to knock down FOXF1 in RT112 and UC6 bladder cancer cell lines to develop an in vitro model for assessment of metastatic potential. Next-generation sequencing and hierarchical clustering analysis were used to identify differentially altered genes secondary to FOXF1 knockdown. 186 biologically curated pathways were interrogated with internal validation to elucidate downstream biologic mechanisms of metastasis. RESULTS: FOXF1 was a top differentially expressed gene in the discovery cohort with 3.6-fold lower expression in nodal metastases than paired primary tumors (n=33, p<0.001). Multivariable analyses in two validation cohorts (total n=128) indicated that FOXF1 underexpression was associated with worse cancer-specific (p=0.046) and overall survival (p=0.006). Murine orthotopic xenografts (n=13) established from human bladder cancer cell lines (UC3, UC6, UC14) showed FOXF1 underexpression in metastatic deposits compared with primary tumors (p=0.004). Hierarchical clustering identified 40 differentially expressed genes between FOXF1-knockdown bladder cancer cell lines and their corresponding controls. Biological pathway interrogation showed differential enrichment for genes associated with mitogen-activated protein kinase signaling, focal adhesion and other carcinogenic pathways in FOXF1-knockdown cells compared with controls (normalized enrichment score ≥1.3). CONCLUSIONS: We identify and characterize FOXF1 as a novel regulatory molecule that drives bladder cancer metastasis. This may be modulated through alterations in intracellular signaling and cellular adhesion. FOXF1 may serve as a prognostic biomarker that can identify patients at impending risk for metastasis who may benefit from more aggressive management. Source of Funding: The University of Texas MD Anderson SPORE in Genitourinary Cancer P50CA091846, NIH/NCI under P30CA016672 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e655-e655 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anirban P. Mitra More articles by this author Andrea Kokorovic More articles by this author Tanner S. Miest More articles by this author Vikram M. Narayan More articles by this author Debasish Sundi More articles by this author Amy Lim More articles by this author Sharada Mokkapati More articles by this author Colin P. N. Dinney More articles by this author Expand All Advertisement Loading ...