Implementing cell-free DNA of pancreatic cancer patient-derived organoids for personalized oncology
Dantes, Z., Yen, H. Y., Pfarr, N., Winter, C., Steiger, K., Muckenhuber, A., Hennig, A., Lange, S., Engleitner, T., Ollinger, R., Maresch, R., Orben, F., Heid, I., Kaissis, G. A., Shi, K., Topping, G. J., Stogbauer, F., Wirth, M., Peschke, K., Papargyriou, A., Rezaee-Oghazi, M., Feldmann, K., Schafer, A. P. G., Ranjan, R., Lubeseder-Martellato, C., Stange, D. E., Welsch, T., Martignoni, M. E., Ceyhan, G. O., Friess, H., Herner, A., Liotta, L., Treiber, M., von Figura, G., Abdelhafez, M., Klare, P., Schlag, C., Algul, H., Siveke, J. T., Braren, R. F., Weirich, G., Weichert, W., Saur, D., Rad, R., Schmid, R., Schneider, G., and Reichert, M. (2020). JCI Insight 5. doi: 10.1172/jci.insight.137809
One of the major challenges in using pancreatic cancer patient-derived organoids (PDOs) in precision oncology is the time from biopsy to functional characterization. This is particularly true for biopsy specimen with limited tumor cell yield, typical characteristics of biopsies from endoscopic ultrasound-guided fine needle aspirations (EUS-FNAs).Here, we tested conditioned media of individual PDOs for cell-free tumor DNA (cfDNA) to detect driver mutations already early on during the expansion process in order to accelerate the genetic characterization of PDOs as well as subsequent functional testing. Importantly, genetic alterations detected in the PDO supernatant, collected as early as 72h after biopsy, recapitulate the mutational profile of the primary tumor indicating suitability of this approach to subject PDOs to drug testing in a reduced timeframe. In addition, we demonstrate that this workflow is practicable even in patients of whom the amount of tumor material was not sufficient for molecular characterization by established means.Our findings demonstrate that generating PDOs from very limited biopsy material permits molecular profiling and drug testing. With our approach this can be achieved in a rapid and feasible fashion with broad implications in clinical practice.