Multi-compartment organoids : an in vitro model of physiological cell coculture

Details

Supervisors

Demoustier-Champagne, Sophie ; Wirtz, Denis

Faculty

Ecole polytechnique de Louvain

Degree label

Master [120] : ingénieur civil biomédical, à finalité spécialisée

Abstract

Context: Progress in the understanding, diagnosis and treatment of many diseases and conditions is currently hindered by a shortage of reliable and physiologically relevant in vitro models. This thesis will focus on three diseases (gestational trophoblastic neoplasia (GTN), endometriosis and ovarian cancer) where several cell types and extracellular matrices (ECM) have key roles in disease development and, thus, must be included in the in vitro organoid model. Objectives: The goal of this thesis will be to expand the novel multi-compartment organoid model developed in the Wirtz/Wu lab (Johns Hopkins University) to include multiple cell types, organoid compartments, and ECM compositions to mimic the tissue microenvironment for healthy and diseased tissues. Experiments: For GTN organoids, GTN cancer cells were cocultured with im- mune populations identified in histological tissue sections (macrophages or NK cells). Four different conditions (including the control) mimicking key steps of the immune recruitment process were studied by modulating the compartmental location where immune cells were seeded. For endometrial and fallopian tube organoids, the respective epithelial cells were cocultured with gynecologic stro- mal cells. Mechanical and paracrine signaling were examined in these organoids by modulating the compartments where epithelial and stromal cells were seeded, including adding a new third compartment to the organoid architecture. Results: Our results for the GTN organoids demonstrated that the model mim- icked the different stages of the immune recruitment cascade to a solid tumor and evaluated the potential of different immune cell types as future immune therapies for GTN. The results demonstrated that additional work in the area of NK cell therapies against GTN may be successful in the future. The endometrial and fallop- ian tube organoid experiments demonstrated an important regulation of epithelial proliferation caused by stromal cell paracrine signaling that will pave the way for further studies about endometriosis and ovarian cancer. Discussion: In the future this tunable model could be incorporated as (1) an important additional screening for new immunotherapies as an intermediate between conventional 2D assays to in vivo models, particularly in solid tumors. It can also (2) be used to explore the cell-cell interactions driving disease progression in a cell and ECM controlled environment, such as endometriosis and ovarian cancer which we have shown here may be regulated by stromal-epithelial interactions.