| dc.description.abstract | In the United States, cancer deaths have dropped by 27% in the last 20 years. Although there has been great progress, effective treatment options for metastatic colorectal cancer (CRC) are still limited, and stage 4 cancers continue to have critically low patient survival rates. CRC metastasis is a very complex and patient-specific disease; therefore, it is necessary to build bioengineering models to better understand it and design more effective, targeted treatments. In this PhD. thesis, I first utilized materials science approaches to develop the SHArD (superhydrophobic array device) system: an easily tunable, engineered substrate to culture physiologically relevant mammalian cell aggregates between tens to thousands of cells each. Two versions of the device were fabricated to culture circulating tumor cell (CTC) clusters and spheroids. The spheroids and CTC cluster models cultured in the SHArD were demonstrated to be more physiologically relevant than those cultured using techniques in the literature.
Then, a computational approach was used to investigate the effects of hormones present during pregnancy on increased cancer aggressiveness and advanced disease in pregnant patients. In vitro experimentation was used to link pregnancy levels of prolactin to increased JAK2/STAT3 and JAG1/NOTCH1 signaling, resulting in increased EMT and cancer stemness. A computational model of the JAK2/STAT3 signaling cascade was built and fit to the in vitro data to understand what parts of the signaling cascade were most sensitive to changes in prolactin during pregnancy and what proteins can serve as molecular targets for reducing cancer aggressiveness in pregnant CRC patients. These two projects converged in a novel therapeutic approach for metastasis prevention via a dual affinity liposomal drug delivery system. Different surface moieties allow the nanoparticle to tether loosely to a carrier cell under FSS, and then bind to the target cell strongly and transfer to its surface. This system significantly killed cancer cells in whole blood via TRAIL-induced apoptosis. Overall, by converging techniques from several different fields, I designed two engineered models of colorectal cancer to aid in developing effective and patient-specific treatments, such as the dual affinity system, with the goal of improving metastasis prevention and patient prognosis. | |
