2024 AIChE Annual Meeting
Development and Optimization of a Modular Microfluidic Device to Study the Effects of Fluid Shear Stress on Metastatic ER+ Breast Cancer
Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of breast cancer cases and relies on the estrogen receptor for proliferation and tumor growth. Of these patients, most will respond to endocrine therapies designed to specifically target the estrogen receptor; however, some develop a resistance to endocrine therapy following metastatic spread. Metastatic cancer is associated with poor patient prognoses and accounts for about 90% of cancer-related deaths. The underlying mechanisms driving endocrine resistance are currently unknown; however, it is suspected that metastasizing cancer cells are exposed to biochemical and biophysical cues that alter their phenotype. One such biophysical force is fluid shear stress (FSS), which prior studies have suggested enhanced proliferation and a pro-survival phenotype at the metastatic site. Most approaches to study the effects of FSS on cancer cells rely on the two-dimensional (2D) culture of cells and interrogation directly after FSS exposure, which does not adequately recapitulate the three-dimensional (3D) growth and cell-to-cell interactions of the tumor microenvironment (TME) or allow for the long-term effects of FSS to be studied. Recent work has shown the potential for the use of 3D spheroids, small aggregates of cancer cells, to mimic what is occurring in the TME. The goal of this study is to develop a modular microfluidic platform capable of first exposing cancer cells to well-defined magnitudes FSS and then growing the cells as 3D spheroids in an array of ~400 circular traps to determine the long-term effect of FSS on metastatic cancer. Initial efforts focused on the optimization of the microfluidic approach including (i) incorporation of a thiol-acrylate (TA) hydrogel scaffold to support 3D growth and (ii) adjusting flowrates of the aqueous and oil phase to ensure proper cell encapsulation. Both sheared and non-sheared MCF-7 cells (a model ER+ cell line) were grown as 3D spheroid for 7 days followed by terminal immunostaining for the proliferative marker Ki67. Both the sheared and non-sheared cohorts were successfully cultured across multiple biological replicates resulting in viable cells in 7 days. Initial results highlight a difference in Ki67 signaling between the sheared and non-sheared cohorts suggesting that exposure to FSS altered the behavior of ER+ breast cancer cells grown as 3D spheroids.