Hyperactive Rac1 drives MAPK-independent proliferation in melanoma by assembly of a mechanosensitive dendritic actin network

摘要: Cancer cells use a variety of mechanisms to subvert growth regulation and overcome environmental challenges. Often, these same enable cancer also develop resistance targeted therapies. Here, we describe how hyperactivating mutation the Rac1 GTPase (Rac1P29S) harnesses Rac19s role as regulator actin polymer assembly sustain cell cycle progression in limiting conditions. This proliferative advantage supports metastatic colonization melanoma confers insensitivity inhibitors mitogen-activated protein kinase (MAPK) pathway, frequent target for treatment. Rac1P29S bypasses MAPK axis through mechanism that necessitates cell-matrix attachment, however, does not depend on integrin-mediated focal adhesion signaling. Even without involvement canonical signaling, carrying show elevated traction upon drug treatment require mechanical from their surrounding matrix gain advantage. We an alternative arm mechanosensing, whereby polymerization against minimal rigidity organizes biochemical cues drive signals. Hyperactivation by P29S channels this pathway Arp 2/3-dependent formation constrained brush network results inactivation tumor suppressor NF2/Merlin. These data suggest mechanosensitive can be hijacked circumvent adverse conditions foreign microenvironments or