Integratedin silicoand 3Din vitromodel of macrophage migration in response to physical and chemical factors in the tumor microenvironment

Abstract

<jats:title>Abstract</jats:title><jats:p>Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions, however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an <jats:italic>in silico</jats:italic> model that couples chemokine-mediated signaling with mechanosensing networks to explain our <jats:italic>in vitro</jats:italic> observations. The model proposes IL-8, CCL2 and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, <jats:italic>in vitro</jats:italic> macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2, or to the co-addition of a sub-optimal concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated <jats:italic>in silico</jats:italic> and 3D <jats:italic>in vitro</jats:italic> approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies.</jats:p>