Extensive DNA sequencing has led to an unprecedented view of the diversity of individual genomes and their evolution among patients with clear cell renal cell carcinoma (ccRCC).

To understand subclonal architecture and dynamics of patient-derived two-dimensional (2D) and three-dimensional (3D) ccRCC models in vitro, in order to determine whether they mirror ccRCC inter- and intratumor heterogeneity.

We have established a comprehensive platform of living renal cancer cell models from ccRCC surgical specimens.

We confirmed the concordance of 2D and 3D patient-derived cell (PDC) models with the original tumor tissue in terms of histology, biomarker expression, cancer driver mutations, and copy number alterations. We addressed inter- and intrapatient heterogeneity by analyzing clonal dynamics during serial passaging.

In-depth genetic characterization verified the presence of heterogeneous cell populations, and revealed a high degree of similarity between subclonal compositions of monolayer and organoid cell cultures and the corresponding parental ccRCCs. Clonal dynamics were evident during serial passaging of cells in vitro, suggesting that PDC cultures can offer insights into evolutionary potential and treatment susceptibility of ccRCC subclones in vivo. Proof-of-concept drug profiling using selected ccRCC-targeted therapy agents highlighted patient-specific vulnerabilities in PDC models that could not be anticipated by interrogating commercially available cell lines.

We demonstrate that PDC models mirror inter- and intratumor heterogeneity of ccRCC in vitro. Based on our findings, we envision that the use of these models will advance our understanding of the trajectories that cause genetic diversity and their consequences for treatment on an individual level.

In this study, we developed two- and three-dimensional patient-derived models from clear cell renal cell carcinoma (ccRCC) as “mini-tumors in a dish.” We show that these cell models retain important features of the human ccRCCs such as the profound tumor heterogeneity, thus highlighting their importance for cancer research and precision medicine.

European urology focus. 2019 Jun 29 [Epub ahead of print]

Hella A Bolck, Claudia Corrò, Abdullah Kahraman, Adriana von Teichman, Nora C Toussaint, Jack Kuipers, Francesca Chiovaro, Viktor H Koelzer, Chantal Pauli, Wolfgang Moritz, Peter K Bode, Markus Rechsteiner, Niko Beerenwinkel, Peter Schraml, Holger Moch

Department of Pathology and Molecular Pathology, University Hospital and University of Zurich, Zurich, Switzerland., NEXUS Personalized Health Technologies, ETH Zurich, Zurich, Switzerland; SIB Swiss Institute of Bioinformatics, Basel, Switzerland., SIB Swiss Institute of Bioinformatics, Basel, Switzerland; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., InSphero AG, Schlieren, Switzerland., Department of Pathology and Molecular Pathology, University Hospital and University of Zurich, Zurich, Switzerland. Electronic address: .