Abstract

Convective Transport and Binding of Extracellular Vesicles Establish Biologically Relevant Spatial Gradients

Steven C. George, Professor, University of California, Davis

Extracellular vesicles (EVs) are small (50-150 nm diameter) composite particles secreted by cells and comprised of a lipid-based membrane surrounding an aqueous core.  The membrane and core can each incorporate a wide range of molecules (e.g., proteins, nucleic acids) that can impact cellular function; thus, EVs can impact in vivo biology, but have also generated significant excitement for their potential theranostic (therapeutic and diagnostic) applications in cancer. How EVs are transported (convection, diffusion, and binding) within the extracellular space is poorly understood.  We hypothesized that EVs are transported predominantly by convection through the interstitium and could establish a spatial gradient via binding to laminin through integrins alph3beta1 and alpha6beta1 expressed on their surface. Our early experimental studies demonstrate EV binding to a laminin-rich extracellular matrix (ECM) increases as the malignant potential of the cellular source increases (MCF10A, MCF10DCIS, MCF10CA1). Binding of the EV to the ECM generates an observable spatial gradient, which impacts the migration of M2-like differentiated macrophages.  The magnitude of the gradient is partially abrogated by blocking antibodies to alpha3beta1 and alpha6beta1 integrin subunits. Examination of EV interstitial transport will enhance our understanding of the dynamic tumor microenvironment and could present new targets for early-stage disease.