title: SNX9 promotes metastasis by enhancing cancer cell invasion via differential regulation of RhoGTPases.
abstract: Despite current advances in cancer research, metastasis remains the leading factor in cancer-related deaths. Here, we identify sorting nexin 9 (SNX9) as a new regulator of breast cancer metastasis. We detected an increase in SNX9 expression in human breast cancer metastases compared with primary tumors and demonstrated that SNX9 expression in MDA-MB-231 breast cancer cells is necessary to maintain their ability to metastasize in a chick embryo model. Reciprocally, SNX9 knockdown impairs the process. In vitro studies using several cancer cell lines derived from a variety of human tumors revealed a role for SNX9 in cell invasion and identified mechanisms responsible for this novel function. We showed that SNX9 controls the activation of RhoA and Cdc42 GTPases and also regulates cell motility via the modulation of well-known molecules involved in metastasis, namely RhoA-ROCK and N-WASP. In addition, we have discovered that SNX9 is required for RhoGTPase-dependent, clathrin-independent endocytosis, and in this capacity, can functionally substitute to the bona fide Rho GAP, GRAF1 (GTPase Regulator Associated with Focal Adhesion Kinase). Together, our data establish novel roles for SNX9 as a multifunctional protein scaffold that regulates, and potentially coordinates, several cellular processes that together can enhance cancer cell metastasis.
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas. 6000 Harry Hines Blvd. Dallas, TX 75390-9039 nawal.bendris@utsouthwestern.edu sandra.schmid@utsouthwestern.edu.
authors.forename: Nawal
authors.initials: N
authors.lastname: Bendris
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Karla C
authors.initials: KC
authors.lastname: Williams
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas. 6000 Harry Hines Blvd. Dallas, TX 75390-9039.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Reis
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas. 6000 Harry Hines Blvd. Dallas, TX 75390-9039.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Welf
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas. 6000 Harry Hines Blvd. Dallas, TX 75390-9039.
authors.forename: Ping-Hung
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS- Universités Montpellier 1 et 2, Montpellier, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Lemmers
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS- Universités Montpellier 1 et 2, Montpellier, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: H S
authors.initials: HS
authors.lastname: Leong
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas. 6000 Harry Hines Blvd. Dallas, TX 75390-9039 nawal.bendris@utsouthwestern.edu sandra.schmid@utsouthwestern.edu.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Schmid