(The) effects of physical constraint on fibroblast phenotypes in the matrix under the stimulation of cancer secretome

Abstract

The biophysical properties of the tumor microenvironment (TME) have been increasingly focused on due to their potential impacts on cancer progression. Biophysical cues in the TME such as stiffness, extracellular matrix (ECM) structure, and solid stress not only play a role in the regulation of cancer cells but also modulate the formation and activation of cancer-associated fibroblasts (CAFs). However, the effect of the physical constraint (PC) of the matrix on the activation of CAFs remains ambiguous. In this study, we investigated the transformation of normal fibroblasts into a CAF-like phenotype under the stimulation of cancer secretome with or without PC. We found that in the PC condition, stimulated fibroblasts caused local ECM disruption and reduced matrix stiffness, leading to less activation of the mechanical signaling pathway. Meanwhile, without PC, fibroblasts were able to induce stiffened matrix and thus much more mechanically active. Interestingly, this PC-free condition also induced a remarkably high expression profile of ECM-remodeling genes in fibroblasts. Our findings indicate the importance of PC in the induction of different CAF phenotypes and suggest the necessary consideration of PC in building models for CAFs studying.