Mechanics- and morphology-mimicking microchannel models of tumor microenvironments

Abstract

Approximately 600,000 cancer-related deaths will occur in 2019 within the United States. As the second leading cause of death nationally, there is high demand for novel therapies to tackle the diseases. However, efforts have not been successful as oncological therapies have the lowest probability of success through clinical trials. Researchers have pointed blame to the inability of current models to accurately predict clinical translation. Traditional monocultures on treated plastics and immunodeficient mice have been the gold standard to study cancer cell behaviors, but their flaws have shifted much research into developing three-dimensional in vitro models. These models can be engineered to capture the complexity of the tumor microenvironment with great control over specific parameters, allowing for more translational studies of cancer behaviors in physiologically relevant systems.

In this thesis, we took into consideration the structure of tubular tissues by considering them cylinders within a matrix, molding microchannels within materials to simulate the structure of these tissues. We then highlighted the importance of tubular tissue geometry in two ways: 1) we studied the influence of a vessel-like constraint on tumor emboli growth and morphology, demonstrating how the mechanical interplay between the emboli and vessel-like geometry can direct its growth and morphology and 2) we developed an organotypic mammary duct model that can recapitulate key features of breast cancer progression that is currently absent from literature.

The promise of 3D in vitro models would ultimately lead to tools that can elucidate new targets for therapies and provide a means to test these therapies in the most clinically translatable ways. Presently, however, these models are simple in design. Typical methods include embedding single cells or a cellular aggregate into a matrix. Although this can well represent a solid tumor within the connective tissue, it fails to take into consideration the structure of important tissues, specifically in the case of tubular tissues. Lymphatic vasculature and mammary ducts are tubular tissues that play significant roles in cancer: both are regions where cancer cells originate.