Abstract 171: Prostate cancer organoids from KUCaP patient-derived xenograft(PDX) series enables us to genetic engineering human-derived cellular models

Abstract

Abstract Introduction and Objectives Cancer organoids are expected to be valuable models that recapitulate intratumor heterogeneity and the phenotypic diversity of the disease ex vivo. However, the establishment rate of prostate cancer (PCa) organoids directly from clinical specimens are still low, and we need to improve. Patient-derived xenograft model (PDX) is widely used as a human-derived in vivo model, but genetic engineering is impossible, limiting its use. We aimed to develop a method to stably grow prostate cancer organoids from PDX and evaluate the feasibility of gene engineering using PDX-derived organoids. Materials and Methods KUCaP PDX series, which were established from castration-resistant prostate cancer patient tissues, were used to establish organoids. Eight organoids from eight models of KUCaP PDX were established and maintained for at least three passages. Organoids were reinjected into immunodeficient mice to establish organoid-derived xenograft (ODX) with 100% efficacy. We compared histopathological and molecular characteristics of primary patient tumors, PDX tumors, organoids, and ODX tumors. We conducted whole exome sequencing and RNA sequencing to assess the genomic profiles across the models. Firefly luciferase was introduced into organoids to show the feasibility of genetic engineering. Results Pathological findings were similar across the models derived from the same patient. WES analysis revealed most of the mutations detected in the matched patient tumors and organoids. Hierarchical clustering of RNA sequencing showed that the primary tumors, PDX tumors, organoids, and ODX tumors derived from the same patient cluster, which indicates that even after clonal selection during the establishment of organoids, the basic molecular feature of the model is maintained (Figure). Firefly luciferase was successfully introduced in seven out of seven tested organoids and imaged the ODX tumors from these organoids in vivo. Conclusions Organoids were established with a high success rate using PDX. Firefly luciferase was successfully introduced, showed the feasibility of genetic engineering using prostate cancer organoids. Matched PDX and organoids of PCa recapitulate the basic molecular features of primary human PCa. PDX-derived organoids of PCa, which enables genetic engineering of human-derived cellular models, which could be a valuable tool to enhance PCa research. Citation Format: Takuro Sunada, Takayuki Goto, Takayuki Sumiyoshi, Akamatsu Shusuke, Takashi Kobayashi. Prostate cancer organoids from KUCaP patient-derived xenograft(PDX) series enables us to genetic engineering human-derived cellular models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 171.