PMID- 35118587 OWN - NLM STAT- MEDLINE DCOM- 20220615 LR - 20221226 IS - 1699-3055 (Electronic) IS - 1699-048X (Print) IS - 1699-048X (Linking) VI - 24 IP - 7 DP - 2022 Jul TI - Phenotypical screening on metastatic PRCC-TFE3 fusion translocation renal cell carcinoma organoids reveals potential therapeutic agents. PG - 1333-1346 LID - 10.1007/s12094-021-02774-8 [doi] AB - PURPOSE: Translocation renal cell carcinoma (tRCC) is a subtype that occurs predominantly in children and young individuals. Metastatic tRCC occurring in young patients is more aggressive than that occurring in older patients, and there are still no effective therapies. Organoids can mimic original tissues and be assessed by high-throughput screening (HTS). We aimed to utilize patient-derived organoids and HTS to screen drugs that can be repurposed for metastatic tRCC with PRCC-TFE3 fusion. METHODS: Tumor tissues were obtained from treatment-naive metastatic tRCC patients who underwent surgery. Histopathology and fluorescence in situ hybridization (FISH) confirmed the tRCC. Organoids derived from the dissected tissues were cultured and verified by FISH and RNA-seq. HTS was performed to seek promising drugs, and potential mechanisms were explored by RNA-seq and cell-based studies. RESULTS: We successfully established a metastatic tRCC organoid with PRCC-TFE3 fusion, a common fusion subtype, and its characteristics were verified by histopathology, FISH, and RNA-seq. An HTS assay was developed, and the robustness was confirmed. A compound library of 1816 drugs was screened. Eventually, axitinib, crizotinib, and JQ-1 were selected for further validation and were found to induce cell cycle arrest and apoptosis. RNA-seq analyses of posttreatment organoids indicated that crizotinib induced significant changes in autophagy-related genes, consistent with the potential pathogenesis of tRCC. CONCLUSIONS: We established and validated organoids derived from tissues dissected from a patient with metastatic tRCC with PRCC-TFE3 fusion and achieved the HTS process for the first time. Crizotinib might be a targeted therapy worthy of exploration in the clinic for metastatic tRCC with PRCC-TFE3 fusion. Such organoid and HTS assays may represent a promising model system in translational research assisting in the development of clinical strategies. CI - (c) 2022. The Author(s). FAU - Cao, Chuanzhen AU - Cao C AD - Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli 17#, Chaoyang District, Beijing, 100021, People's Republic of China. FAU - Lan, Xiaomei AU - Lan X AD - K2 Oncology Co. Ltd., Beijing, 100176, People's Republic of China. FAU - Shang, Bingqing AU - Shang B AD - Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli 17#, Chaoyang District, Beijing, 100021, People's Republic of China. FAU - Jiang, Weixing AU - Jiang W AD - Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli 17#, Chaoyang District, Beijing, 100021, People's Republic of China. FAU - Guo, Lei AU - Guo L AD - Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China. FAU - Zheng, Shan AU - Zheng S AD - Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China. FAU - Bi, Xingang AU - Bi X AD - Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli 17#, Chaoyang District, Beijing, 100021, People's Republic of China. FAU - Zhou, Aiping AU - Zhou A AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli 17#, Beijing, 100021, People's Republic of China. zhouaiping_cicams@yeah.net. FAU - Sun, Zhijian AU - Sun Z AD - K2 Oncology Co. Ltd., Beijing, 100176, People's Republic of China. zjsun@k2oncology.com. FAU - Shou, Jianzhong AU - Shou J AUID- ORCID: 0000-0002-1148-2442 AD - Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli 17#, Chaoyang District, Beijing, 100021, People's Republic of China. shoujzh2021@163.com. LA - eng GR - 2016ZX09101094/National Science and Technology Major Project of China/ GR - 82072837/National Natural Science Foundation of China/ PT - Journal Article DEP - 20220203 PL - Italy TA - Clin Transl Oncol JT - Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico JID - 101247119 RN - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (TFE3 protein, human) RN - 53AH36668S (Crizotinib) SB - IM MH - Aged MH - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism MH - *Carcinoma, Renal Cell/drug therapy/genetics/metabolism MH - Crizotinib/pharmacology MH - Humans MH - In Situ Hybridization, Fluorescence MH - *Kidney Neoplasms/diagnosis/drug therapy/genetics MH - Oncogene Proteins, Fusion/genetics MH - Organoids MH - Translocation, Genetic PMC - PMC9192364 OTO - NOTNLM OT - High-throughput screening OT - Metastatic OT - Organoid OT - Translocation renal cell carcinoma COIS- The authors have declared no conflicts of interest. EDAT- 2022/02/05 06:00 MHDA- 2022/06/16 06:00 PMCR- 2022/02/03 CRDT- 2022/02/04 05:55 PHST- 2021/09/30 00:00 [received] PHST- 2021/12/31 00:00 [accepted] PHST- 2022/02/05 06:00 [pubmed] PHST- 2022/06/16 06:00 [medline] PHST- 2022/02/04 05:55 [entrez] PHST- 2022/02/03 00:00 [pmc-release] AID - 10.1007/s12094-021-02774-8 [pii] AID - 2774 [pii] AID - 10.1007/s12094-021-02774-8 [doi] PST - ppublish SO - Clin Transl Oncol. 2022 Jul;24(7):1333-1346. doi: 10.1007/s12094-021-02774-8. Epub 2022 Feb 3.