PhD defence G.S. (Gilles) van Tienderen

Summary:

Liver cancer is a heterogeneous cancer with a dismal prognosis due to late diagnosis and limited treatment options. Novel in vitro models that can recapitulate the tumor are essential in increasing our understanding of liver cancer. Therefore, the research presented in this thesis focuses on modeling various facets of liver cancer behavior in vitro. To this extent, tumor organoid technology and decellularization of multiple tissues that are relevant for liver cancer (i.e. liver cancer, adjacent liver, lung, and lymph nodes) are employed. On the organoid side, we describe a multi-center analysis on the state of the art of liver cancer organoid technology, suggesting improvements for establishment and expansion. Furthermore, we improve liver cancer organoid models by addition of immune cells and improving morphological recapitulation. On the decellularization side, we uncover novel findings about liver cancer ECM through an integrative molecular and mechanical approach. Furthermore, we combine liver cancer organoids with ECM in both a local tumor and metastatic setting to create in vitro models that recapitulate various aspects of liver cancer behavior, including transcriptome, drug response, and protein production. Lastly, we create an ECM-based hydrogel and combine this with microfluidics to create microcapsules containing size-standardized organoids. In all, there is no one-model fits all philosophy within tumor modeling, and it is crucial to consider the question that needs to be addressed and apply that to the inclusion of aspects within the model. Ultimately, (pre)clinical translation of liver cancer biology through organoid-centered models will improve patient outcomes.