(169i) Implantable Scaffolds to Engineer a Pre-Metastatic Niche for Early Detection and Treatment of Breast Cancer Metastasis

Breast cancer metastasis continues to remain the highest contributor to breast cancer-related deaths worldwide. A major limitation in developing life-preserving timely interventions is the scarcity of robust technologies capable of early detection of metastatic disease as well as model systems that allow systematic screening and examination of factors contributing to tumor metastasis in a controlled setting.  Prior to colonization of a metastatic site, a “pre-metastatic niche” that consists of cells, soluble factors, and extracellular matrix components is established, acting as a supportive microenvironment for tumor cell homing and colonization. Importantly, the existence of this niche indicates that metastasis to a particular site is not random but is pre-determined. This view indicates that an environment could be engineered to attract these metastatic cells. To this end, we previously developed microporous poly(lactide-co-glycolide) (PLG) scaffolds that induce metastatic tumor cell homing to a defined site (e.g., subcutaneous space or peritoneal fat pad) in vivo for early detection of metastatic disease and subsequently reduce tumor burden in major organs (e.g., lung). However, translation of this technology to the clinical setting necessitates biomaterials with greater long term stability. To address this need, we developed microporous poly(ε-caprolactone) (PCL) scaffold implants that exhibit little to no degradation over a period of 14 weeks when implanted subcutaneously in tumor free mice, demonstrating stability of the implant for long term studies and eventual translation. Moreover, we have demonstrated that PCL scaffolds recruit metastatic tumor cells and reduce tumor burden in major organs (e.g., lung) when implanted in the subcutaneous space of tumor bearing mice. We are investigating the utility of PCL implants in mouse models that recapitulate the application of this technology in the clinical setting. For example, we have demonstrated that PCL scaffolds recruit metastatic tumor cells when implanted subcutaneously for longer time periods in vivo (e.g., ~ 1 month) prior to tumor induction - a situation that mimics the chronic response to a scaffold implant. Further, to mimic clinical disease progression, we have established a post-surgical model of breast cancer metastasis incorporating PCL scaffolds implants and are currently examining their ability to influence survival. In sum, these implants with early detection and therapeutic potential could be easily integrated into current breast cancer disease management plans and hold significant promise to lead to a reduction in breast cancer mortality in the near future.