Myosin-actin pattern links matrix stiffness to GFAT2-hyaluronan metabolism

While dysregulated extracellular matrix deposition and stiffening are known to drive tumor progression, breast cancer cells can persist, relapse, and metastasize to soft microenvironments. The distinct strategies that tumor cells adapted to soft matrices remain to be further explored. Here, we report that breast tumor cells exploit soft matrices to activate GFAT2-mediated hyaluronan metabolism that can modulate macrophages. This process is driven by the upregulation of GFAT2 expression through enhanced nuclear translocation of NF-κB and XBP1s, coupled with elevated GFAT activity and subsequent hyaluronan production via suppressed AMPKα phosphorylation. Mechanistically, the expression and activity of GFAT2 are jointly modulated by the total cellular levels of myosin and F-actin. More specifically, the ROCK-Rac1 balance, which can regulate both the cortical-to-cytoplasmic ratio of active myosin and the circumferential arrangement of cortical F-actin, mediates the NF-κB-XBP1s-GFAT2 signaling axis. Furthermore, our in silico modeling validates that the spatial pattern of myosin directly regulates the orientation of cortical F-actin arrangement. These findings establish a novel mechano-metabolic link between matrix compliance and detrimental mediators-NF-κB/XBP1s, GFAT, and hyaluronan-uncovering a potential microenvironmental reprogramming strategy adopted by tumor cells in soft niches.