RT Journal Article SR Electronic T1 Hyperactive Rac1 drives MAPK-independent proliferation in melanoma by assembly of a mechanosensitive dendritic actin network JF bioRxiv FD Cold Spring Harbor Laboratory SP 326710 DO 10.1101/326710 A1 Ashwathi S. Mohan A1 Kevin M. Dean A1 Stacy Y. Kasitinon A1 Tadamoto Isogai A1 Vasanth Siruvallur Murali A1 Sangyoon J. Han A1 Philippe Roudot A1 Alex Groisman A1 Erik Welf A1 Gaudenz Danuser YR 2018 UL http://biorxiv.org/content/early/2018/05/22/326710.abstract AB Cancer cells use a variety of mechanisms to subvert growth regulation and overcome environmental challenges. Often, these same mechanisms enable cancer cells to also develop resistance to targeted therapies. Here, we describe how a hyperactivating mutation of the Rac1 GTPase (Rac1P29S) harnesses Rac1’s role as a regulator of actin polymer assembly to sustain cell cycle progression in growth limiting conditions. This proliferative advantage supports metastatic colonization of melanoma cells and confers insensitivity to inhibitors of the mitogen-activated protein kinase (MAPK) pathway, a frequent target for melanoma treatment. Rac1P29S bypasses the MAPK axis through a mechanism that necessitates cell-matrix attachment, however, does not depend on integrin-mediated focal adhesion assembly and focal adhesion kinase signaling. Even without involvement of canonical adhesion signaling, cells carrying the Rac1P29S mutation show elevated traction upon drug treatment and require mechanical resistance from their surrounding matrix to gain a proliferative advantage. We describe an alternative arm for cell mechanosensing, whereby actin polymerization against a matrix of minimal rigidity organizes biochemical cues to drive proliferative signals. Hyperactivation of Rac1 by the P29S mutation channels this pathway in melanoma through Arp 2/3-dependent formation of a constrained actin brush network that results in the inactivation of tumor suppressor NF2/Merlin. These data suggest an alternative mechanism for mechanosensitive growth regulation that can be hijacked by cancer cells to circumvent the adverse conditions of foreign microenvironments or drug treatment.