For many types of cancer, the formation of distant metastasis marks the disease stage where treatment is no longer curative. Currently, there are limited methods to detect dissemination and colonization of tumor cells to distal sites until macroscopic tumors are radiologically evident. To improve detection of metastasis at early and more treatable stages, we developed biomaterial scaffolds that recruit breast metastatic tumor cells in mouse models, acting as a diagnostic. Our long-term objective is to use the scaffolds as a tool for the early detection of metastatic disease and to monitor the niche environment to determine responsiveness to therapy. We propose to employ the scaffold to dissect cellular components that mediate tumor cell recruitment and phenotype, prior to and following therapy. Implantable scaffolds recruit tumor cells in vivo prior to their detection in solid organs. The recruitment of tumor cells to a defined site serves as a defined and accessible location to detect metastatic progression and facilitates study into mechanisms of niche development. Tumor cells isolated from the scaffold have distinct migration, invasion, and dissemination behaviors relative to cells isolated from the primary tumor but are phenotypically similar to those found in the lung. Elements reported in the natural metastatic niche, including myeloid derived suppressor cells and macrophages, have been found within the implanted scaffolds. Clear changes in the populations of immune cells at the scaffold were identified as metastatic disease progressed. We propose the following specific aims.
Specific Aim 1 will investigate the cellular composition and heterogeneity of implant-captured cells during disease progression. Implantable scaffolds recruit tumor cells in vivo before their detection at other metastatic sites. We propose to dissect the cellular composition of both physiologic and synthetic niches through single cell analyses, and to assess their contribution to tumor cell recruitment. The phenotypes and heterogeneity of these cells will be monitored over time to determine sub-populations that can predict the status of the physiologic metastatic niche.
Specific Aim 2 will test the hypothesis that the scaffolds can monitor responsiveness to therapy. Therapeutic resistance occurs with even the most promising drugs, largely due to heterogeneity of the tumor cells.
Aim 2 will correlate tumor and stromal cell phenotypes in the synthetic niche with survival outcomes in the mice following treatment with eribulin chemotherapy. We will identify specific genes and cell phenotypes that are highly differentiated between responsive and resistant mice.
Specific Aim 3 will investigate safety and cell recruitment in the scaffolds in a Phase I clinical trial. We propose to implant scaffolds in adult females diagnosed with metastatic breast cancer to evaluate the potential of the scaffolds as a clinical diagnostic. The safety of the scaffolds will be assessed, and we will study their ability to recruit heterogenous populations of tumor and stromal cells. Collectively, these studies support our ultimate goals of facilitating early detection and effective treatment of metastatic breast cancer.
There is a critical need to identify early metastatic disease and chemoresistance in order to administer the most efficacious treatments to patients and improve 5-year survival rates, which are currently around 30% for metastatic breast cancer. We are proposing the use of an implanted biomaterial scaffold that serves as a synthetic pre-metastatic niche through the early recruitment of tumor cells and acts as a surrogate for the physiological niche, where dynamics in cell heterogeneity can be used as a diagnostic for metastatic disease. The translation of these implants from murine models to human subjects will demonstrate the clinical potential of such a system as a source for recruited tumor and stromal cells that can be analyzed for the early detection of metastatic breast cancer and identification of chemoresistance.
