Patient derived organoids to model rare prostate cancer phenotypes

• Published in: Nature communications Vol. 9; no. 1; pp. 2404 - 10
• Main Authors: Puca, Loredana, Bareja, Rohan, Prandi, Davide, Shaw, Reid, Benelli, Matteo, Karthaus, Wouter R., Hess, Judy, Sigouros, Michael, Donoghue, Adam, Kossai, Myriam, Gao, Dong, Cyrta, Joanna, Sailer, Verena, Vosoughi, Aram, Pauli, Chantal, Churakova, Yelena, Cheung, Cynthia, Deonarine, Lesa Dayal, McNary, Terra J., Rosati, Rachele, Tagawa, Scott T., Nanus, David M., Mosquera, Juan Miguel, Sawyers, Charles L., Chen, Yu, Inghirami, Giorgio, Rao, Rema A., Grandori, Carla, Elemento, Olivier, Sboner, Andrea, Demichelis, Francesca, Rubin, Mark A., Beltran, Himisha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.06.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 631/67/1059; 631/67/70; Animals; Antineoplastic Agents - pharmacology; Cancer; Castration; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Drug screening; Epigenetics; Epigenomics - methods; Gene Expression Profiling - methods; Genomics - methods; Humanities and Social Sciences; Humans; Lesions; Male; Metastases; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Molecular chains; multidisciplinary; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; Organoids; Organoids - metabolism; Organoids - pathology; Patients; Phenotype; Phenotypes; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Science; Science (multidisciplinary); Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04495-z

A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes. There are few available models to study neuroendocrine prostate cancer. Here they develop and characterize patient derived organoids from metastatic lesions, use these models to show the role of EZH2 in driving neuroendocrine phenotype, and perform high throughput organoid screening to identify therapeutic drug combinations.