Mechanotransduction of interstitial fluid stresses and effects on tumor cell migration

Abstract

Breast cancer incidence in the United States is I in 8, and over 90% of breast cancer related deaths are due to metastases, secondary tumors at a site distant from the primary tumor. Metastasis formation requires carcinoma cells to navigate through the tumor microenvironment and invade the surrounding stroma. Migration is a highly orchestrated process in which cells are guided by both internal signals and signals from the microenvironment. Hence, understanding the mechanisms that guide cell migration in response to various stimuli in the tumor and stromal microenvironments is key to developing therapies that prevent tumor cell migration and render cancer more treatable. Osmotic and hydrostatic pressure gradients within the extracellular matrix (ECM) drive flow of interstitial fluid through the ECM. Elevated osmotic pressure, lymphatic collapse, solid stress, and increased microvascular permeability contribute to elevated interstitial fluid pressure (IFP) during carcinoma progression, and high intratumoral IFP leads to pressure gradients at the tumor margin, which drive fluid flow that emanates from the tumor core to drain in the surrounding stroma. In this thesis, we explore the effect of interstitial flow (IF) on tumor cell migration. We developed a microfluidic platform to apply repeatable, robust IF through tissue constructs consisting of human metastatic breast cancer cells embedded within a 3D collagen type I matrix. We implemented the microfluidic device to validate CCR7-mediated autologous chemotaxis as a mechanism that guides downstream migration in response to IF. However, we identified a separate competing pathway that drives cell migration upstream (rheotaxis). Rheotaxis results from asymmetry in matrix adhesion stress that is required to balance fluid drag imparted by IF on tumor cells. Thus, autologous chemotaxis, mediated by chemical transport, and rheotaxis, mediated by fluid stresses, compete to direct cell migration downstream or upstream in response to IF. Our results provide insight into mechanotransduction in 3D porous media and into the mechanisms by which asymmetries in matrix adhesion tension guide cell migration. Furthermore, our results demonstrate that the consideration of IF is crucial for understanding and treating metastatic disease. Key words: Interstitial flow, mechanotransduction, tumor cell migration, microfluidics.