Guanine nucleotide exchange factors for Rho GTPases (RhoGEFs) as oncogenic effectors and strategic therapeutic targets in metastatic cancer

Abstract

Metastatic cancer cells dynamically adjust their shape to adhere, invade, migrate, and expand to generate secondary tumors. Inherent to these processes is the constant assembly and disassembly of cytoskeletal supramolecular structures. The subcellular places where cytoskeletal polymers are built and reorganized are defined by the activation of Rho GTPases. These molecular switches directly respond to signaling cascades integrated by Rho guanine nucleotide exchange factors (RhoGEFs), which are sophisticated multidomain proteins that control morphological behavior of cancer and stromal cells in response to cell-cell interactions, tumor-secreted factors and actions of oncogenic proteins within the tumor microenvironment. Stromal cells, including fibroblasts, immune and endothelial cells, and even projections of neuronal cells, adjust their shapes and move into growing tumoral masses, building tumor-induced structures that eventually serve as metastatic routes. Here we review the role of RhoGEFs in metastatic cancer. They are highly diverse proteins with common catalytic modules that select among a variety of homologous Rho GTPases enabling them to load GTP, acquiring an active conformation that stimulates effectors controlling actin cytoskeleton remodeling. Therefore, due to their strategic position in oncogenic signaling cascades, and their structural diversity flanking common catalytic modules, RhoGEFs possess unique characteristics that make them conceptual targets of antimetastatic precision therapies. Preclinical proof of concept, demonstrating the antimetastatic effect of inhibiting either expression or activity of βPix (ARHGEF7), P-Rex1, Vav1, ARHGEF17, and Dock1, among others, is emerging.