Forces exerted and transduced by cancer‐associated fibroblasts during cancer progression

Although it is well‐known that cancer‐associated fibroblasts (CAFs) play a key role in regulating tumor progression, the effects of mechanical tissue changes on CAFs are understudied. Myofibroblastic CAFs (myCAFs), in particular, are known to alter tumor matrix architecture and composition, heavily influencing the mechanical forces in the tumor microenvironment (TME), but much less is known about how these mechanical changes initiate and maintain the myCAF phenotype. Additionally, recent studies have pointed to the existence of CAFs in circulating tumor cell clusters, indicating that CAFs may be subject to mechanical forces beyond the primary TME. Due to their pivotal role in cancer progression, targeting CAF mechanical regulation may provide therapeutic benefit. Here, we will discuss current knowledge and summarize existing gaps in how CAFs regulate and are regulated by matrix mechanics, including through stiffness, solid and fluid stresses, and fluid shear stress. Phenotypic and genetic changes occur in cancer‐associated fibroblasts (CAFs) as a result of external mechanical forces associated with primary tumor growth and the metastatic cascade. CAFs can also initiate changes to the tumor microenvironment (TME) which result in altered mechanical dynamics to cancer cells and the surrounding matrix, sometimes forming a positive feedback loop that maintains the CAF phenotype.