Abstract
70% of advanced breast cancer patients will develop bone metastases, which accounts for ~90% of cancer related mortality. Breast cancer circulating tumor cells (CTC) establish metastatic tumors in the bone after a close interaction with local bone marrow cells including endothelial cells, pericytes and osteoblasts. In vitro recapitulation of the bone microenvironment could provide new insights helping in the development of novel therapeutic strategies. Gene expression interrogation, migration and proliferation assays were performed to establish how osteoblast-like cells (OLC) and pericyte-like cells (PLC) affected primary breast cancer cell (3384T) phenotype. Results indicate that PLC drive 3384T cancer cells to an invasive and migratory phenotype, while OLC induce a quiescence state, thus recapitulating the different phases of the in vivo bone metastatic process. Once these correlations were established and in order to exploit these interactions, a design-build-test approach was used to engineer a microphysiological system (MPS) for the study of breast cancer metastasis to bone. The biomimetic device was fabricated using rapid prototyping techniques and consists of an osteoblast compartment containing osteocytes derived from primary bone marrow-derived mesenchymal stem cells (hBM-MSC) upstream of a vascular membrane comprised of endothelial cells and PLC and located above a CTC well. MPS can sustain flow at biomimetic rates without leaks and house 4 different cell populations with compatible media. The device also presents an architecture in which cells can be imaged and tracked live on the device allowing for real time interrogation of the desired cell types without disrupting the system while its resealable form factor permits non-terminal retrieval of any of the cell component.