Tensile force field plays a crucial role in local invasion of tumor cells through a mechano-chemical coupling mechanism

Abstract

Cancer metastasis starts from early local invasion, during which tumor cells detach from the primary tumor, penetrate the extracellular matrix (ECM), and then invade neighboring tissues. However, the cellular mechanics in the detaching and penetrating processes have not been fully understood, and the underlying mechanisms that influence cell polarization and migration in the 3D matrix during tumor invasion remain largely unknown. In this study, we employed a dual tumor-spheroids model to investigate the cellular mechanisms of the tumor invasion. Our results revealed that the tensional force field developed by the active contraction of cells and tissue plays pivotal roles in tumor invasion, acting as the driving force for remodeling the collagen fibers during the invasion process. The remodeled collagen fibers promoted cell polarization and migration because of stiffening of the fiber matrix. The aligned fibers facilitated tumor cell invasion and directed migration from one spheroid to the other. Inhibiting/shielding the cellular contractility abolished matrix remodeling and re-alignment and significantly decreased tumor cell invasion. By developing a coarse-grained cell model that considers the mutual interaction between cells and fibers, we predicted the tensional force field in the fiber network and the associated cell polarization and cell-matrix interaction during cell invasion, which revealed a mechano-chemical coupling mechanism at cellular level of the tumor invasion process. Our study highlights the roles of cellular mechanics at the early stage of tumor metastasis, and may provide new therapeutic strategies for cancer therapy.