Tracing clonal dynamics reveals that 2D and 3D patient-derived cell models capture tumor heterogeneity of clear cell renal cell carcinoma

Patient Summary In this study, we developed 2D and 3D 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.BackgroundExtensive 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). ObjectiveTo understand subclonal architecture and dynamics of patient-derived 2D and 3D ccRCC models in vitro in order to determine whether they mirror ccRCC inter- and intra-tumor heterogeneity.Design, Setting, and ParticipantsWe have established a comprehensive platform of living renal cancer cell models from ccRCC surgical specimens.Outcome Measurements and Statistical AnalysisWe 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 intra-patient heterogeneity by analyzing clonal dynamics during serial passaging.Results and LimitationIn-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. Indeed, drug profiling in monolayer cultures, microtissues and ccRCC organoids revealed patient-specific response patterns that could not be anticipated by interrogating commercially available cell lines.Conclusions We demonstrate that PDC models mirror inter- and intra-tumor 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.