Rapid multilayer microfabrication for modeling organotropic metastasis in breast cancer.

ABSTRACT

Triple-negative breast cancer (TNBC) is one of the most insidious forms of breast cancer with high rates of metastasis, resulting in major mortalities in breast cancer patients. To better understand and treat TNBC metastasis, investigation of TNBC interactions with blood vasculatures is crucial. Among multiple metastatic processes, a step of TNBC exit from the blood vessels ('extravasation') in the pre-metastatic organs determines the final site of the metastasis. Here, we present a rapid multilayer microfabrication method of transferring a three-dimensional (3D) overhang pattern to a substrate with a sacrificial layer to reconstitute a 3D blood vessel surrounded by the extracellular matrix containing organ-specific parenchymal cells. Bones and lungs are the most common sites of breast cancer metastasis. We modeled organotropic bone and lung metastasis in TNBC by introducing subpopulations of TNBC metastases into a vessel lumen surrounded by osteoblasts, bone marrow derived mesenchymal stem cells, and lung fibroblasts. We found that bone-like microenviroment with osteoblasts and mesenchymal stem cells promoted extravasation of the bone-tropic TNBC cells, whereas the lung-like microenviroment promoted extravasation of the lung-tropic TNBC cells. Given that these organ-specific parenchymal cells do not impact vascular permeability, our results suggest that the parenchymal cells dictate selective extravasation of the bone-tropic or lung-tropic TNBC cells in our system.