The Rho Exchange Factors Vav2 and Vav3 Favor Skin Tumor Initiation and Promotion by Engaging Extracellular Signaling Loops

• DOI: 10.1371/journal.pbio.1001615
• Publication Date: 2013-07-24T15:41:40Z
• Authors: Mauricio Menacho-...; Ramón García-Escu...; Virginia Ojeda; Antonio Abad; Pilar Delgado; Clotilde Costa; Sergio Ruiz; Balbino Alarcón; Jesús M. Paramio; Xosé R. Bustelo
• Keywords: Keratinocytes; Mice, Knockout; 0303 health sciences; Skin Neoplasms; QH301-705.5; 3. Good health; Mice; 03 medical and health sciences; Animals; Biology (General); Proto-Oncogene Proteins c-vav; Research Article; Cell Proliferation; Signal Transduction

The catalytic activity of GDP/GTP exchange factors (GEFs) is considered critical to maintain the typically high activity of Rho GTPases found in cancer cells. However, the large number of them has made it difficult to pinpoint those playing proactive, nonredundant roles in tumors. In this work, we have investigated whether GEFs of the Vav subfamily exert such specific roles in skin cancer. Using genetically engineered mice, we show here that Vav2 and Vav3 favor cooperatively the initiation and promotion phases of skin tumors. Transcriptomal profiling and signaling experiments indicate such function is linked to the engagement of, and subsequent participation in, keratinocyte-based autocrine/paracrine programs that promote epidermal proliferation and recruitment of pro-inflammatory cells. This is a pathology-restricted mechanism because the loss of Vav proteins does not cause alterations in epidermal homeostasis. These results reveal a previously unknown Rho GEF-dependent pro-tumorigenic mechanism that influences the biology of cancer cells and their microenvironment. They also suggest that anti-Vav therapies may be of potential interest in skin tumor prevention and/or treatment.