Tissue-engineered human lymphatic models for the study of breast cancer and obesity
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Abstract
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.
Description
2025