2025 / The role of the lymphatic vasculature in disease has been gaining appreciation in recent years. For example, lymphatic vessels can serve as a route for tumor metastasis to secondary organs. Additionally, obesity is often associated with lymphatic dysfunction. In vitro tissue-engineered models that incorporate lymphatic vessels can be a useful tool to study lymphatics in disease. These models offer several advantages, including the use of human cells, the ability to replicate 3D environments, the incorporation of interstitial fluid flow, and precise control over tissue geometry. Here, I develop multiple tissue engineered models to study lymphatics in the context of breast cancer and obesity. Using a co-culture model with a breast microtumor adjacent to an engineered lymphatic, I investigate the role of the lymphatic endothelium in tumor invasion and vascular escape. Cancer cells that escape into the vessel can present inside, in line with, or outside the lymphatic endothelium and can displace endothelial cells on the vessel wall during this process. The presence of the lymphatic endothelium has an inhibitory effect on breast cancer invasion and escape through both physical and nonphysical mechanisms. Next, to examine how obesity can affect lymphatic solute drainage, I simulate the obesity-associated microenvironment in multiple lymphatic models using tumor necrosis factor-α, cobalt chloride, and oleic acid to model inflammation, hypoxia, and hyperlipidemia, respectively. Simulated obesity directly impairs lymphatic solute drainage rates of engineered lymphatics, likely by damaging endothelial junctions and promoting solute leakage from lymphatics. In contrast, conditioned medium from obesity-treated adipocytes does not affect lymphatic drainage. Surprisingly, co-culturing adipocytes with the lymphatics prevents the harmful effects of simulated obesity on the lymphatics, revealing a potential protective role of adipocytes in obesity-related lymphatic dysfunction. Overall, these model systems elucidate the role of lymphatic vessels in breast cancer and obesity and provide a platform for studying both tumor vascular escape and lymphatic drainage function in disease.

Les métastases sont la principale cause de décès chez les patients atteints d’un cancer. Lors du développement métastatique, les cellules tumorales disséminées (CTD) doivent franchir certaines étapes clés avant de coloniser des organes distants de la tumeur primaire. Notre hypothèse est que la TNC pourrait jouer différents rôles dans la migration des cellules cancéreuses et par conséquent dans le développement métastatique. Considérant l’actine comme un réservoir de facteurs de croissance, la TNC pourrait induire la TEM ainsi que la survie et l’extravasation des cellules tumorales. Cependant, des cellules cancéreuses individualisées localement pourraient répondre à la TNC en initiant des changements rapides menant à un phénotype migratoire de type amiboïde. L’objectif de cette thèse a été d’étudier comment la TNC stimule le développement métastatique dans le cancer du sein au niveau cellulaire et moléculaire en utilisant des modèles tumoraux et cellulaires. / A high TNC expression correlates with lung metastagenicity and was shown to promote experimental lung metastasis, but the underlying mechanisms are poorly understood. The results of my thesis have provided insight into the roles of TNC in metastasis suggesting that TNC contributes to extravasation by impacting on survival, endothelialization, EMT and migration. Moreover, I have identified TGF-β signaling and integrin α9β1 as important pathway and molecule, respectively to be employed by TNC. Whether both molecule/pathway play a similar role in the investigated models of breast cancer, osteosarcoma and glioblastoma remains to be seen.