Use of microfluidics for 3D-culturing of patient-derived prostate cancer tissues and preclinical screening of personalized treatment strategies
Pathology
Cell Biology
Final Report Abstract
Despite progress in the identification of therapeutic targets, the new knowledge has not led to significant changes in prostate cancer (PCa) patient outcomes. This is due to the current PCa models, which are mainly based on the 2D culture of conventional cell lines generated more than 50 years ago. They are obviously not sufficient for the representative therapy testing of clinically highly variable PCa. To address this issue, my previous work focused on the development of 3D PCa research models that could preserve the characteristics of the original patient tumors and enable personalized therapy screening. Although several patient-derived models such as patient-derived xenografts (PDXs) and tumor organoids (PDOs) have been successfully established, the long doubling time and limited amount of the generated materials as well as the time- and cost-intensive procedures impede an extensive therapy screening using those models. This project should connect the microfluidic based “lab-on-a-chip” concept with the novel patient-derived 3D models of PCa to develop representative therapy screening tools for personalized treatment strategies. Microfluidic devices (lab-on-a-chip devices) are microchips composed of several channels containing multiple microwells in which small tumor fragments can be trapped and incubated. Since the team of Prof. Thomas Gervais (Polytechnique Montréal / Canada) has developed the polydimethylsiloxane-based microfluidic chips, which allow survival of micro-dissected tumors (MDT) for more than 15 days without perfusion, researchers at the University Hospital of Montreal and Montreal Cancer Institute (team of Prof. Fred Saad and Prof. Anne-Marie Mes-Masson) focus on experimental process optimization. In the initial part of this project, culturing of all currently available 3D PCa models including spheroids, PDOs and MDTs from patient´s tissue and PDX on microfluidic chips were attempted. The fabrication of the devices was continuously adapted and modified for different types of 3D models and biological processes for significant therapy evaluation. Afterwards, up to 128 PDOs or 32 MDTs of primary tumors could be treated with max. four different therapeutic strategies in one chip. This means, multiple therapeutic strategies incl. irradiation can be tested at the same time using only a pair of microchips, which require only very small quantities of biological materials and drugs. Finally, the therapeutic response of the treated tumors could be evaluated in a multiplexed manner by diverse assays. To evaluate the in vivo-like property of the microfluidic system, the therapeutic response of the tumors treated within the chips was compared with the response of the equally treated xenografts. We expect that the microfluidic-based lab-on-a-chip technology will not only replace the large scale of animal experiment to prove a therapeutic concept but also yield predictive therapy screening tools for the individualized treatment of PCa.
