Therapeutic benefit of scaffolds that capture metastatic tumor cells in vivo
Grace Bushnell - Department of Biomedical Engineering Final Oral Examination
For most cancers, the formation of distant metastasis is the point at which clinical treatment shifts from curative intent to extending progression free survival. Physicians are currently unable to diagnose metastasis until disseminated tumor cells affect the function of a target organ as a secondary tumor. This dissertation describes a novel approach where implantable biomaterial scaffolds are used to recruit metastatic tumor cells for early detection prior to colonization of solid organs. This recruitment of tumor cells to a defined site can not only serve as a platform for detection, but can also have therapeutic effects and be used as a platform to study metastatic processes. This dissertation describes work in each of these three areas including using an implantable biomaterial scaffold for early detection, therapeutic benefit, and a platform to study metastasis. The therapeutic benefit of scaffolds was demonstrated by scaffold implantation significantly enhancing disease-free survival in a murine model of triple negative breast cancer. Myeloid derived suppressor cells were the key population of immune cells whose capture at the scaffold and reduction in the spleen and primary tumor lead to enhanced survival. In an effort to probe the contributions of various immune cell types to the formation and maintenance of the pre-metastatic and metastatic niche in vivo, a gene delivery approach was utilized to alter the immune microenvironment of the scaffold and investigate the recruitment of tumor cells, finding reduced immune and tumor cell recruitment with IL-10 delivery and developing a model of tumor cell recruitment that is dependent upon the proportion of each immune cell type in the niche. Additional efforts to use the scaffold to study metastasis included studying scaffold captured tumor cells relative to tumor cells derived from other locations. Scaffold captured tumor cells were a highly aggressive population of metastatic tumor cells similar to those found in a metastatic lung, underscoring the use of the scaffold as a sampling location for metastatic disease that is reflective of tumor cell phenotype in solid organs. Next, biomaterial scaffolds were also validated in transgenic models of both breast and pancreatic cancer to identify immune dysregulation as a function of tumor burden, recruit tumor cells, and to reduce tumor burden. Finally, non-invasive ultrasound imaging and subsequent spectral analysis techniques were applied to identify changes in the scaffold associated with tumor burden and tumor cell recruitment. Taken together, this body of work supports that the implantable biomaterial scaffold technology provides a robust and novel approach for the early detection of metastatic disease in both breast and pancreatic cancer, therapy to divert both pre-metastatic niche forming immune cells and tumor cells themselves to an ectopic site and away from solid organs, and as a platform to study mechanisms of the pre-metastatic niche and metastasis.
Chair: Dr. Lonnie Shea
Chair: Dr. Lonnie Shea
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