(The) effect of cell-mediated ECM remodeling in glycated collagen on the induction of cancer associated fibroblast

Abstract

The extracellular matrix (ECM) in tumor microenvironment tends to be stiffer, caused by increased collagen crosslinking. Dysregulated ECM can initiate altered fibroblast activation that might lead to cancer associated fibroblast (CAFs) with high contractile phenotype. However, the subsequent effect of cell-mediated ECM remodeling on the induction of CAFs remain not fully understood. Herein, we investigated the effect of physical matrix remodeling by cell-mediated contractile force on previously induced phenotype alteration by matrix glycation, finally lead to CAFs-like phenotype. To confirm this, we constructed two kinds of physical remodeling (PR) controlled conditions in glycated collagen matrix. As a result, we demonstrated that glycation-mediated matrix remodeling can induce altered fibroblast activation in a mechno-physical way, then subsequently, matrix contraction due to cell-mediated ECM remodeling can precipitate the CAFs-like phenotype by enabling sustained activation. Interestingly, rather than matrix stiffening by glycation itself, the ability of cell-mediated matrix contraction in glycated matrix has a decisive role on CAFs induction by preserving mechanical tension. Our finding suggests that glycation-based in vitro dynamic ECM models can be used to study fibroblast activation or CAFs-like phenotype in human diseases undergoing both physiological and pathological ECM remodeling.