Abstract 3885: Establishment, characterization and drug response of primary and metastatic prostate organoids
Authors: Karkampouna Sofia , Manna Federico la , Zoni Eugenio , Beimers Lijkele , Kloen Peter , Wetterwald Antoinette , Grosjean Joël , Klima Irena , Cecchini Marco Giovanni , Spahn Martin , Thalmann George Niklaus , Julio Marianna Kruithof- de 
Published: July 2017

Introduction & objectives: Prostate cancer (PCa)-associated mortality results from metastasis to bone and resistance to androgen deprivation or cytotoxic therapy. Despite early detection of primary PCa, advanced castration resistant prostate cancer (CRPC) and bone metastases (BM) are detected in 10% of patients already at the time of initial diagnosis. The majority of recurrences might be due to cancer cells with stem cell-like properties (cancer stem cell-like, CSC-like). These could be therapy-resistant in a dormant state at the primary site or have metastasize prior to diagnosis of the primary tumor. CSC-like cells are the most tumorigenic and metastatic, however, current treatments target the differentiated tumor bulk cells. Understanding the mechanisms of PCa tumor initiation and metastasis by CSC-like cells is crucial for proper prognosis of high risk patient groups.

Materials & methods: To model CSC-like cells we generated organoids from patient-derived tissues (here termed as “canceroids”) and established patient-derived xenografts (PDXs). Canceroids were derived from bulk tumor tissues; primary PCa, bone metastasis from PCa tissue (BM-PCa), established PDX models LAPC9 and BM18 and lymph node (LN) metastasis from PCa (LAPC4) PDX models. Cytotoxic compounds and androgen inhibitors are tested on the canceroids from different BM or LN tissues using viability assays (CellTiter Glo assay) and 3D imaging by confocal and light sheet microscopy.

Results: We have generated several canceroid lines from human primary PCa and from established PDX models that maintain key features of the CSC-like cells, previously characterized on the tumor itself (AR, PSA, Cytokeratins). The luminal phenotype of BM18 is evidently maintained in the BM18 canceroids, based on positive cytokeratin (CK)18 and absent CK5 expression. LAPC4 organoids contain CK5 and CK18 cells, in line with the mixed basal and luminal phenotype. Imaging of PSA and cytokeratin distribution confirms the luminal phenotype of the canceroids. BM18 and LAPC9 canceroids are maintained both in presence and absence of dihydrotestosterone indicating that androgen independent growth properties of the tumor are conserved in the canceroids. Viability assays indicate that canceroids respond to chemotherapeutics (cabacitaxel, docetaxel) and partially to hormone inhibitors (abiraterone, enzalutamide).

Conclusions: Identification of the oncogenic properties of metastatic CSC-like (sub)populations has both prognostic and therapeutic applications. Establishment of CSC-derived organoids is the first step towards routine derivation from metastasis or primary PCa tissues as a potential platform for personalized drug compound evaluation.

Citation Format: Sofia Karkampouna, Federico la Manna, Eugenio Zoni, Lijkele Beimers, Peter Kloen, Antoinette Wetterwald, Joël Grosjean, Irena Klima, Marco Giovanni Cecchini, Martin Spahn, George Niklaus Thalmann, Marianna Kruithof- de Julio. Establishment, characterization and drug response of primary and metastatic prostate organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3885. doi:10.1158/1538-7445.AM2017-3885