Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation

• Published in: The Journal of cell biology 2017-12, Vol.216 (12), p.4331-4349
• Main Authors: Donnelly, Sara K, Cabrera, Ramon, Mao, Serena P H, Christin, John R, Wu, Bin, Guo, Wenjun, Bravo-Cordero, Jose Javier, Condeelis, John S, Segall, Jeffrey E, Hodgson, Louis
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; ADP-Ribosylation Factor 6; ADP-Ribosylation Factors - genetics; ADP-Ribosylation Factors - metabolism; Animals; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cell Adhesion; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cells; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Integrin beta1 - genetics; Integrin beta1 - metabolism; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Proteins; Proto-Oncogene Proteins c-vav - genetics; Proto-Oncogene Proteins c-vav - metabolism; rac GTP-Binding Proteins - deficiency; rac GTP-Binding Proteins - genetics; Rats; Rho Guanine Nucleotide Exchange Factors - genetics; Rho Guanine Nucleotide Exchange Factors - metabolism; Signal Transduction; Tissues; Tumors
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201704048

The initial step of metastasis is the local invasion of tumor cells into the surrounding tissue. Invadopodia are actin-based protrusions that mediate the matrix degradation necessary for invasion and metastasis of tumor cells. We demonstrate that Rac3 GTPase is critical for integrating the adhesion of invadopodia to the extracellular matrix (ECM) with their ability to degrade the ECM in breast tumor cells. We identify two pathways at invadopodia important for integrin activation and delivery of matrix metalloproteinases: through the upstream recruiter CIB1 as well as the downstream effector GIT1. Rac3 activity, at and surrounding invadopodia, is controlled by Vav2 and βPIX. These guanine nucleotide exchange factors regulate the spatiotemporal dynamics of Rac3 activity, impacting GIT1 localization. Moreover, the GTPase-activating function of GIT1 toward the vesicular trafficking regulator Arf6 GTPase is required for matrix degradation. Importantly, Rac3 regulates the ability of tumor cells to metastasize in vivo. The Rac3-dependent mechanisms we show in this study are critical for balancing proteolytic activity and adhesive activity to achieve a maximally invasive phenotype.