RESEARCH PROJECTS

Metastatic cancers are chemoresistant, involving complex interplay between disseminated cancer cell aggregates and the distant organ microenvironment (extracellular matrix and stromal cells). Conventional metastasis surrogates (scratch/wound healing, Transwell migration assays) lack 3D architecture and ECM presence. Metastasis studies can therefore significantly benefit from biomimetic 3D in-vitro models recapitulating the complex cascade of distant organ invasion and colonization by collective clusters of cells. We aimed to engineer reproducible and quantifiable 3D models of highly therapy-resistant cancer processes: (i) colorectal cancer liver metastasis; and (ii) breast cancer lung 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.

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.

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.

Brain aneurysms can be treated with embolic coils using minimally invasive approaches. It is advantageous to modulate the biologic response of platinum embolic coils. Macrophages are the most prevalent immune cell type that coordinate the greater immune response to implanted materials. To test this hypothesis, we analyze the number and type of infiltrating macrophages in FCC or BPC devices implanted in a rabbit elastase aneurysm model.