The influence of matrix stiffness on the behavior of brain metastatic breast cancer cells in a biomimetic hyaluronic acid hydrogel platform. 
Breast cancer brain metastasis marks the most advanced stage of breast cancer no longer considered curable with a median survival period of ∼4-16 months.  Apart from the genetic susceptibility (subtype) of breast tumors, brain metastasis is also dictated by the biophysical/chemical interactions of tumor cells with native brain microenvironment, which remain obscure, primarily due to the lack of tunable biomimetic in vitro models.  To address this need, we utilized a biomimetic hyaluronic acid (HA) hydrogel platform to elucidate the impact of matrix stiffness on the behavior of MDA-MB-231Br cells, a brain metastasizing variant of the triple negative breast cancer line MDA-MB-231.  We prepared HA hydrogels of varying stiffness (0.2-4.5 kPa) bracketing the brain relevant stiffness range to recapitulate the biophysical cues provided by brain extracellular matrix.  In this system, we observed that the MDA-MB-231Br cell adhesion, spreading, proliferation, and migration significantly increased with the hydrogel stiffness.  We also demonstrated that the stiffness based responses of these cells were mediated, in part, through the focal adhesion kinase-phosphoinositide-3 kinase pathway.  This biomimetic material system with tunable stiffness provides an ideal platform to further the understanding of mechanoregulation associated with brain metastatic breast cancer cells.  © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1832-1841, 2018.