Dissecting the tumour microenvironment of pancreatic cancer and predicting chemotherapy-response using patient-derived organoids

• Applicant: Dr. Christoph Gerdes
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569642258

Pancreatic ductal adenocarcinoma (PDAC) is extremely lethal and projected to become the second leading cause of cancer mortality in Western countries. The central hypothesis for this project is that new signatures and predictive biomarkers have the potential to improve overall treatment response and identify optimized personalized treatment options in PDAC. Thus, the aim will be to find new biomarkers for treatment selection using patient-derived organoids. The project spans 24 months and will use samples from the phase-II trial PASS-01. In December 2020, the PASS-01 trial opened to compare mFOLFIRINOX versus Gemcitabine/Nab-Paclitaxel in treatment-naive patients with metastatic PDAC. A total of 160 patients enrolled. All participants underwent whole-genome sequencing (WGS), RNA sequencing (RNASeq), and patient-derived organoid (PDO) development (105 PDOs). Over 80% yielded successful genomes, more than 72% produced consistent RNA signatures, and 9% displayed KRAS wild-type while 21% were Basal-like. These samples and additional samples from previous trials will be used in this project. Four objectives define the project‘s scope. First, genomic, transcriptomic, and single-cell datasets of primary tumors and their PDOs will be compared in terms of KRAS status, genomic subtypes, ploidy, driver mutations, transcriptomic subtype, tumor stage, and patient clinical data. Particular attention will be paid to the “hybrid state” in both patient tumors and PDOs, including single-cell analysis to clarify how frequently these states appear. Second, the project will investigate whether treatment response can be inferred from PDO-based profiling. This goal tries to discover predictive biomarkers enabled by organoid pharmacotyping and transcriptomic analysis, seeking potential responders to FOLFIRINOX or Gem-Pac. Alternative regimens will be evaluated for those whose PDOs show resistance. Third, the tumor microenvironment’s role in cell plasticity and therapy response will be addressed by single-cell analysis of PDOs and matched tumors. This approach aims to identify how cell states shift absent the TME. Fourth, the plan includes a high-throughput (HT) drug screen of 105 PASS-01 PDOs and additional PDOs to discover new drug candidates. It will be possible to assess therapeutic vulnerabilities, especially those that may arise from KRAS inhibitors. The final six months will focus on analysis of drug sensitivity, correlating hits with genomic and transcriptomic data, thereby establishing a comprehensive functional landscape of PDAC. All in all, PDAC diagnostics remain fundamentally inadequate, treatment options are far from optimal, and only a small fraction of patients gain access to targeted therapies. There is a pressing need for novel drugs and improved treatment selection. Consequently, this project aims to find new biomarkers that guide the optimal use of existing therapies and to identify additional potential treatment strategies.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Host: Professor Faiyaz Notta, Ph.D.