Pd14-06 Targeting Lass2: A New Way Out for Chemoresistant Bladder Cancer

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (PD14)1 May 2024PD14-06 TARGETING LASS2: A NEW WAY OUT FOR CHEMORESISTANT BLADDER CANCER Shi Fu, Haifeng Wang, Jiansong Wang, and Hongjin Shi Shi FuShi Fu , Haifeng WangHaifeng Wang , Jiansong WangJiansong Wang , and Hongjin ShiHongjin Shi View All Author Informationhttps://doi.org/10.1097/01.JU.0001009472.76470.8c.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The benefits of first-line, cisplatin-based chemotherapy for muscle-invasive bladder cancer are limited due to intrinsic or acquired resistance to cisplatin. Increasing evidence has revealed the implication of cancer stem cells in the development of chemoresistance. However, the underlying molecular mechanisms remain to be elucidated. We previously found that LASS2 is closely related to chemotherapy efficacy in bladder cancer, and we hope to elucidate the mechanism and find chemo-sensitization methods in this study. METHODS: Data from our cohorts and published datasets were used to evaluate the clinical characteristics of LASS2. We isolated primary cells from a chemotherapy-resistant patient and sorted CD44+ALDH1A1+ bladder cancer stem cells (BCSCs) by flow cytometry. The roles of LASS2 in BCSCs were evaluated by spheroid formation assay, soft agar colony formation assay, EdU assay, and cisplatin sensitivity assay. Then, pathway reporter array, luciferase reporter assay, and ChIP assay were used to determine the transcriptional process. Immunofluorescence, immunoblotting, co-immunoprecipitation, mass spectrometry, protein half-life assay, and enzyme activity assay were used to determine the LASS2 signaling. Cell- and patient-derived xenograft models were used to investigate the effect of LASS2 overexpression and a combination of XAV939 on cisplatin sensitization and tumor growth. RESULTS: Patients with low LASS2 expression respond poorly to cisplatin-based chemotherapy and had a worse prognosis. Loss of LASS2 confers a stem-like phenotype and contributes to cisplatin resistance. Overexpression of LASS2 results in inhibition of self-renewal ability of BCSCs and increased their sensitivity to cisplatin. Mechanistically, LASS2 inhibits PP2A activity and dissociates PP2A from β-catenin, preventing the dephosphorylation of β-catenin and leading to the accumulation of cytosolic phospho-β-catenin, which decreases the transcription of the downstream genes ABCC2 and CD44. LASS2-overexpressing adenovirus combined with a tankyrase inhibitor synergistically inhibits tumor growth and restores cisplatin sensitivity. It has been proven to be a safe treatment through animal evaluation. CONCLUSIONS: Targeting LASS2 is an effective strategy to overcome cisplatin resistance and inhibit tumor growth in bladder cancer. Download PPT Source of Funding: This research is supported by the National Natural Science Foundation of China (Grant No. 81860452, Grant No. 82260609) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e355 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Shi Fu More articles by this author Haifeng Wang More articles by this author Jiansong Wang More articles by this author Hongjin Shi More articles by this author Expand All Advertisement PDF downloadLoading ...