Perfusion bioreactor enabled fluid-derived shear stress conditions for novel bone metastatic prostate cancer testbed.

Critical understanding of the complex metastatic cascade of prostate cancer is necessary for the development of a therapeutic interventions for treating metastatic prostate cancer. Increasing evidence supports the synergistic role of biochemical and biophysical cues in cancer progression at metastases. The biochemical factors such as cytokines have been extensively studied in relation to prostate cancer progression to the bone; however, the role of shear stress-induced by interstitial fluid around bone extracellular matrix has not been fully explored as a driving factor for prostate cancer metastasis. Shear stress governs various cellular processes, including cell proliferation and migration. Thus, it is essential to understand the impact of fluid-derived shear stress on the aggressiveness of prostate cancer at the metastatic stage. Here, we report development of a three-dimensional (3D) in-vitro dynamic cell culture system to recapitulate the microenvironment of prostate cancer bone metastasis, to understand the cause of modulation in cell response under fluid-derived shear stress. We observed an increased human mesenchymal stem cells (hMSCs) proliferation and differentiation rate under dynamic culture. We observed that hMSCs under static culture form cell agglutinates, whereas under dynamic culture, hMSCs exhibited a directional alignment with broad and flattened morphology. Next, we observed increased expression of mesenchymal to epithelial transition (MET) biomarkers in bone metastasized prostate cancer models as well as large changes in cellular and tumoroid morphologies with shear stress. Evaluation of cell adhesion proteins indicated that the altered cancer cell morphologies resulted from the constant force pulling due to increased E-Cadherin and phosphorylated Focal adhesion kinase (FAK) proteins under shear stress. Collectively, we have successfully developed a 3D in-vitro dynamic model to recapitulate the behavior of bone metastatic prostate cancer under dynamic conditions.