PD53-05 BLADDER CANCER TUMOROIDS AND NORMAL UROTHELIAL ORGANOIDS AS NEAR-PATIENT MODELS TO STUDY BLADDER CANCER TUMORIGENESIS AND PREDICT TREATMENT RESPONSE

Abstract

You have accessJournal of UrologyCME1 May 2022PD53-05 BLADDER CANCER TUMOROIDS AND NORMAL UROTHELIAL ORGANOIDS AS NEAR-PATIENT MODELS TO STUDY BLADDER CANCER TUMORIGENESIS AND PREDICT TREATMENT RESPONSE Maryam Akbarzadeh, Mathijs Scholtes, Ameneh Bazrafshan, Tokameh Mahmoudi, and Tahlita Zuiverloon Maryam AkbarzadehMaryam Akbarzadeh More articles by this author , Mathijs ScholtesMathijs Scholtes More articles by this author , Ameneh BazrafshanAmeneh Bazrafshan More articles by this author , Tokameh MahmoudiTokameh Mahmoudi More articles by this author , and Tahlita ZuiverloonTahlita Zuiverloon More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002630.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clinical outcome linked to bladder cancer (BC) stage, grade and histology can be attributed to distinct molecular profiles and a better understanding of these molecular profiles could lead to novel rational treatment strategies. We previously successfully set-up a BC tumoroid and urothelial organoid culture protocol to investigate the biological role of molecular alterations in BC. Here, the aim was to characterize previously established patient-derived tumoroids and normal organoids generated from BC patients with various clinical and molecular background. Additionally, we aimed to investigate whether patient-derived tumoroids can serve as a predictive model to guide patient treatment. METHODS: Tumoroid/organoid cultures and originating tissue were characterized by H&E staining, SNaPshot analysis for hTERT, FGFR3 and PIK3CA hotspot mutations, and copy number aberrations (CNA) analysis using SNP-microarrays. Expression of urothelial differentiation markers was investigated by immunofluorescence (CK5, CK20, GATA3) and qPCR (CD44, CK14, GATA3, FOXA1, UPK3A) in tumoroids/organoids treated with different culture conditions. Originating tissues were characterized by immunohistochemistry (CK5, CK14, GATA3, CK20). Tumoroid ex vivo drug response to cisplatin and FGFR-inhibitor erdafitinib treatment was investigated by AlamarBlue and CellTiter-Glo cell viability assays. RESULTS: Tumor-tumoroid pairs showed corresponding hotspot mutations, CNAs, and similar expression of basal/luminal differentiation markers. In case of divergent differentiation or variant histological subtypes, the tumoroid phenotypically resembled the tissue of origin. Tumoroids generated from cisplatin-resistant patients demonstrated resistance to serum concentrations of cisplatin, while FGFR3-mutant tumoroids responded to erdafitinib treatment. As for organoids, no genetic aberrations were detected in originating normal urothelium and organoids did not acquire CNAs or hotspot mutations over freeze-thaw cycles or several months of ex vivo culturing. The organoids could be differentiated to recapitulate the normal urothelial microanatomy showing lumen formation and spatial organization of luminal/basal cells. CONCLUSIONS: We successfully characterized genetically stable BC tumoroid and urothelial organoid lines that molecularly resemble originating tissues. Additionally, we demonstrated that tumoroids can be used to investigate ex vivo treatment response. Source of Funding: Erasmus MC mRACE Grant and TKI-LSH Match Grant © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e911 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Maryam Akbarzadeh More articles by this author Mathijs Scholtes More articles by this author Ameneh Bazrafshan More articles by this author Tokameh Mahmoudi More articles by this author Tahlita Zuiverloon More articles by this author Expand All Advertisement PDF DownloadLoading ...