Beyond static models: Mechanically dynamic matrices reveal new insights into cancer and fibrosis progression

The dynamic mechanical nature of extracellular matrices (ECMs) is crucial for the mechanosensitive regulation of cell fate. This is evident in pathological conditions such as cancer and fibrosis, which are characterised by highly fibrotic tissue developing over time. This fibrotic progression not only alters tissue mechanics, but also coincides with the reprogramming of resident cells, promoting their differentiation into aberrant phenotypes and increasing drug resistance. Hydrogels, with their tuneable mechanical and biochemical properties, emerge as powerful ECM mimetics to model and study these abnormal, mechanically-driven cell differentiation phenomena. In this review, after establishing how conventional, mechanically static hydrogels contribute to our understanding of the role of altered mechanosensing in cell differentiation during cancer and fibrosis, we explore the research opportunities given by advanced dynamic matrices. Models employing hydrogels that are fast relaxing, plastic or even with temporally switchable mechanics reveal the otherwise hidden role of time-dependent phenomena during disease development.