Committee Chair: Jungwoo Lee
Metastasis is the leading cause of cancer related deaths, yet it remains the most poorly understood aspect of tumor biology. This can be attributed to the lack of relevant experimental models that can recapitulate the complex and lengthy progression of metastatic relapse observed in patients. Mouse models have been widely used to study cancer however they are critically limited to study metastasis. Most models generate aggressive metastasis in the lung without the use of unique cell lines or specialized injection techniques. This limits the ability to study disseminated tumor cells (DTCs) in other relevant metastasis prone tissues. Prolonged observation of the post-dissemination phase of cancer cell biology and the dormant-to-active transition are additional challenges to study in mouse models due to the rapid onset of actively growing primary and secondary tumors that shorten the experimental timeframe. These limitations have left a critical gap in the understanding of metastasis, specifically the long-term bi-directional crosstalk between DTCs and their local microenvironment. Previous findings have demonstrated that subcutaneously implanted inverted colloidal crystal (ICC) hydrogel scaffolds recruit circulating tumor cells and capture metastatic progression. Here I introduce new implantable tissue engineered metastasis models that overcome the fundamental restrictions of existing mouse models and substantiate the role of the tumor niche in the reactivation of dormant DTCs with molecular and cellular detail.
DTC niches were engineered to identify critical niche components that enable metastatic progression. Changing the anatomical location of the implant yielded unique microenvironments with varying levels of metastatic potential. A secondary approach utilized the immunomodulatory properties of ICC scaffolds to assist the transplantation of adult lung and liver tissues into the subcutaneous space for prolonged study of metastasis-relevant tissues. Next, the transplantable nature of scaffold niches was leveraged to investigate DTC dormancy and potential triggers of metastatic relapse. A fully humanized mouse model was developed to explore local niche evolution as human DTCs progressed from single cells to small colonies and overt metastases. The local vasculature and Ly6G+ cells were observed to play important roles during each step of the transition to aggressive proliferation. The effect of adjuvant chemotherapy and surgical disruption on DTCs and their niche was also explored by using a fully immunocompetent mouse model. Lastly, I improved the fabrication of ICC hydrogel scaffolds to make the process more scalable for widespread use. The use of expanded polystyrene beads enabled cheaper, faster, and safer production of ICC hydrogel scaffolds.
Tissue engineering approaches to recreate in vivo DTC microenvironments represent an exciting opportunity to better understand metastasis. The presented models and techniques may be enabling tools to aid in the development of anti-metastasis therapies that significantly benefit patient health.