Translation: Translation using patient-derived organoids
Employing patient-derived organoids as a translational validation platform
Patient-derived organoids (PDOs) faithfully recapitulate key biological features of their parental tumors and serve as a powerful engine for forward and reverse translation in oncology. By bridging conventional in vitro assays, animal models, and clinical studies, PDOs provide a versatile platform for functional validation of therapeutic concepts. Using PDOs, we demonstrated the relevance of a β2-adrenergic–neurotrophin feed-forward loop in PDAC and showed that propranolol significantly reduces PDO viability and enhances the efficacy of gemcitabine (Renz et al., Cancer Cell, 2018). We also supported targeting the KRAS dependency on PTPN11/SHP2, contributing to the initiation of an international phase I/Ib clinical trial (SHERPA trial; Ruess et al., Nature Medicine, 2018). Beyond tumor cell–intrinsic vulnerabilities, we applied PDOs to evaluate CAR-T cell therapies and complex tumor–microenvironment interactions, highlighting their modular integration with immune cells and cancer-associated fibroblasts (Lesch et al., Nature Biomedical Engineering, 2021; Feldmann et al., Gastroenterology, 2021).
Cell-free DNA in PDO supernatant recapitulates patient tumor genomics
A major limitation of patient-derived organoids (PDOs) in precision oncology is the time required from biopsy to molecular and functional characterization, particularly when tumor material from EUS-guided fine-needle aspirations is scarce. To accelerate this process, we analyzed cell-free tumor DNA (cfDNA) released into PDO-conditioned media during early culture. Genetic alterations detected in PDO supernatants as early as 72 hours after biopsy accurately recapitulate the mutational landscape of the parental tumor, even in cases where conventional tissue profiling was not feasible. This approach enables rapid molecular profiling and downstream drug testing from minimal biopsy material, supporting timely clinical implementation of PDO-based precision oncology (Dantes et al., JCI Insight, 2020).
Implementation of a functional precision oncology platform
Despite major advances in precision oncology, the rate of molecularly informed treatment decisions in pancreatic ductal adenocarcinoma (PDAC) remains low. Primary tumor models such as patient-derived organoids (PDOs) enable the addition of a functional and mechanistic layer to precision oncology by allowing systematic genetic and pharmacological interrogation. We established a longitudinal functional precision oncology platform to identify therapy-induced vulnerabilities and demonstrated that chemotherapy-driven tumor cell plasticity dynamically reshapes sensitivity to targeted therapies—even in the absence of selectable genetic biomarkers (Peschke et al., EMBO Molecular Medicine, 2022). These findings highlight tumor plasticity as a tractable and exploitable feature in highly adaptive cancers such as PDAC.
Building on this work, we initiated a Germany-wide patient-derived organoid platform for pancreatic and colorectal cancer within the German Cancer Consortium (DKTK). This platform aims to implement organoid technologies at scale to functionally link tumor biology with clinical outcomes. The DKTK organoid platform is led and coordinated by Max Reichert together with Daniel Stange (Dresden) and Henner Farin (Frankfurt), providing a national infrastructure for functional precision oncology and prospective clinical translation.