Figure 1. Shared signaling responses induced by mechanical cues and mechanisms of chemoresistance in cancer cells.

Mechanical cues that are present in the tumor microenvironment [TME; i.e., mechanical forces or extracellular matrix (ECM) stiffness] are sensed by: (i) membrane receptors, such as integrins; (ii) G protein-coupled receptors (GPCRs); and (iii) ion channels. At the same time, mechanosensors regulate the activity of GFRs, together leading to the activation of major signaling pathways, including RAS, PI3K, FAK, and Hippo. These pathways interact with each other to promote cytoskeleton rearrangement, which is mainly facilitated by the activation of ROCK/Rho, RAC/cdc42, and myosin II, translocation of transcription factors into the nucleus that directly regulate gene expression, and eventually regulation of epithelial-to-mesenchymal transition (EMT) and cancer stemness. Altogether, these mechanically driven responses lead to four main chemoresistance mechanisms: activation of (i) drug efflux and (ii) DNA repair, and alterations in (iii) cell cycle and (iv) apoptosis. Faded structures represent known mechanically regulated pathways in normal cells, while structures shown in full color represent those structures shown to be regulated by mechanical cues in cancer cells. Abbreviation: CSC, cancer stem cell. Created with BioRender.com.