Prostate cancer patient-derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens.

Patient-derived organoids (PDOs) represent promising preclinical models of various tumor types. In the context of prostate cancer (PCa) however, their establishment has been hampered by poor success-rates, which impedes their broad use for translational research applications. Along with the necessity to improve culture conditions, there is a need to identify factors influencing outcomes and to determine how to assess success versus failure in organoid generation. In the present study, we report our unbiased efforts to generate PDOs from a cohort of 81 PCa specimens with diverse pathological and clinical features. We comprehensively analyzed histological features of each enrolled sample (Gleason score, tumor content, proliferation index) and correlated it with organoid growth patterns. We identified improved culture conditions favoring the generation of PCa organoids, yet no specific intrinsic tumor feature was broadly associated with sustained organoid growth. In addition, we performed phenotypic and molecular characterization of tumor-organoid pairs using immunohistochemistry, immunofluorescence, fluorescence in situ hybridization, and targeted sequencing. Morphological and immunohistochemical profiles of whole organoids altogether provided a fast read-out to identify the most promising ones. Notably, primary samples were associated with an initial take-rate of 83% (n=60/72) in culture, with maintenance of cancer cells displaying common PCa alterations, such as PTEN loss and ERG overexpression. These cancer organoids were however progressively overgrown by organoids with a benign-like phenotype. Finally, out of 9 metastasis samples, we generated a novel organoid model derived from a hormone-naive lung metastasis, which displays alterations in the PI3K/Akt and Wnt/ß-catenin pathways and responds to androgen deprivation. Taken together, our comprehensive study explores determinants of outcome and highlights the opportunities and challenges associated with the establishment of stable tumor organoid lines derived from PCa patients.

The Journal of pathology. 2021 May 02 [Epub ahead of print]

Raphaelle Servant, Michele Garioni, Tatjana Vlajnic, Melanie Blind, Heike Pueschel, David C Müller, Tobias Zellweger, Arnoud J Templeton, Andrea Garofoli, Sina Maletti, Salvatore Piscuoglio, Mark A Rubin, Helge Seifert, Cyrill A Rentsch, Lukas Bubendorf, Clémentine Le Magnen

Department of Urology, University Hospital Basel, Basel, Switzerland., Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Switzerland., Department of Urology, St. Claraspital, Basel, Switzerland., Division of Medical Oncology, St. Claraspital, Basel, and Faculty of Medicine, University of Basel, Basel, Switzerland., Department for BioMedical Research, University of Bern, Bern, Switzerland.