(108g) Development of An in Vivo Metastasis Sensor Using Biomaterial Scaffolds

The majority of breast cancer deaths result from metastasis from the primary tumor site, which often cannot be detected until the metastatic cells have colonized one or more sites and affected tissue function. Prior to colonization of a metastatic site, a “pre-metastatic niche” is established, creating a tumor-supportive microenvironment that includes numerous cell types, such as hematopoietic and endothelial progenitor cells and immune cells. Importantly, the existence of the pre-metastatic niche implies that metastasis to a particular site is not random, but it predetermined. Thus, we hypothesized that an environment could be engineered to attract metastatic cells and aimed to develop a biomaterial scaffold that could create a defined in vivo microenvironment recapitulating the pre-metastatic niche in order to attract metastatic tumor cells. Microporous scaffolds composed of poly(lactide-co-glycolide) (PLG), an FDA-approved biodegradable material, were implanted in the peritoneal fat pads or subcutaneous space of female mice containing breast tumors. Tumor cells were stably transfected to express tdTomato and luciferase to enable detection of metastasizing cells. Bioluminescence imaging (BLI) of peritoneal fat pads removed from mice 4 weeks after tumor inoculation demonstrated that tumor cells metastasized to this site if a PLG scaffold was present, yet were not observed in the absence of a scaffold, indicating that the local environment generated by implantation of the scaffold enabled recruitment of metastatic cells. Further modulation of the local population of immune cells through delivery of a lentiviral vector encoding for the chemokine CCL22 from the scaffold increased recruitment of tumor cells, suggesting that tumor cell recruitment was mediated in part through the presence of key immune cell populations within the scaffold. Finally, a light scattering-based imaging technique, inverse-scattering optical coherence tomography (ISOCT), was employed to develop methods for label-free, non-invasive detection of tumor cells upon arrival at the scaffold. ISOCT imaging of tumor-bearing scaffolds ex vivo demonstrated the ability to visualize the tumor cells, and future efforts will be directed toward enabling in vivo detection of scaffold colonization. These data indicate that microporous PLG scaffolds can be used to engineer a pre-metastatic niche in vivo through modulation of the local environment. Coupled with ISOCT imaging, the ability of the scaffolds to recruit metastasizing cells could be used as a sensor to detect the earliest stages of metastatic disease, enabling therapeutic intervention while the disease burden is low.