HOW DO CANCER STEM CELLS EVADE INNATE IMMUNITY?
It is well documented that colorectal cancers, like most others, suppress the immune system and progress. A big focus of immunotherapy has been on adaptive immune cells like T-cells. However, innate immune cells like macrophages are a majority of infiltrating immunocytes within the tumor. We will use tissue engineering to create 3D models of micro-tumors derived from cancer stem cells (patient and cell-line derived), and macrophages. Using this engineered model, we can perform a battery of tests that will help us understand how cancer stem cells and macrophages interact. With this knowledge, we can design more efficacious immunotherapies directed against both cancer stem cells and macrophages to eradicate colorectal cancer.
HOW DOES THE DYNAMIC COLORECTAL MICROENVIRONMENT CONTRIBUTE TO METASTASIS?
Nothing in the body exists in static conditions. Colorectal cancers grow within the intestinal epithelial lumen, which is subject to near constant peristalsis - the motion of the gut that aids in digestion and absorption of nutrients. This dynamic force causes shear stress on the lumen, and hence on the tumor. Mechanical forces such as these are documented to create an environment favorable to cancer progression and metastasis. By building bioreactors to mimic the intestinal epithelium, and subjected tumor micro-tissues to peristasis-induced shear stress, we can study how these forces cause colorectal cancer spread and progression.
ENGINEERING THE NEURAL METASTATIC NICHE IN COLORECTAL TUMORS
Nerves are unique metastatic microenvironments for several cancers. The colorectal environment is densely innervated by the enteric nervous system (which is responsible for intestinal motility). Previously, nerves were thought to be passive modes for metastatic transmission, but more recent research has suggested that colorectal tumors may actively recruit enteric nerves that in turn provide trophic cues, allowing the tumor to grow and propagate. Within this project, we will utilize tissue engineering principles to create the enteric neuronal network that would typically innervate colorectal tumors using neural stem cells. By combining colorectal tumor micro-tissues and engineered nerve plexuses, we can study the peri-neural invasion metastatic phenomenon.
ENGINEERING THE ENTERIC NEURO-IMMUNE NICHE TO STUDY COLONIC MOTILITY
Intestinal motility is a complex interplay between smooth muscle cells and the enteric nervous system (ENS). Muscularis macrophages regularly contact motor neurons, and disruptions in ENS function and intestinal motility are noted in immuno-pathologies of the gut. Macrophages have recently been implicated in the regulation of colonic peristalsis even at homeostasis, although the precise mechanism of interaction and resulting effects on gut motility remains unknown. We will use stem cell and tissue engineering principles to engineer the neuro-immune niche by adapting previous models of creating engineered nerves, and engineered colon tissues. We can then study the effects of neuro-immune crosstalk on colonic motility using real-time force transducer systems, and understand how these change in colonic inflammation.
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