title: β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion.
abstract: BACKGROUND
  For efficient metastatic dissemination, tumor cells form invadopodia to degrade and move through three-dimensional extracellular matrix. However, little is known about the conditions that favor invadopodia formation. Here, we investigated the effect of β-adrenoceptor signaling - which allows cells to respond to stress neurotransmitters - on the formation of invadopodia and examined the effect on tumor cell invasion.
  
  
  METHODS
  To characterize the molecular and cellular mechanisms of β-adrenergic signaling on the invasive properties of breast cancer cells, we used functional cellular assays to quantify invadopodia formation and to evaluate cell invasion in two-dimensional and three-dimensional environments. The functional significance of β-adrenergic regulation of invadopodia was investigated in an orthotopic mouse model of spontaneous breast cancer metastasis.
  
  
  RESULTS
  β-adrenoceptor activation increased the frequency of invadopodia-positive tumor cells and the number of invadopodia per cell. The effects were selectively mediated by the β2-adrenoceptor subtype, which signaled through the canonical Src pathway to regulate invadopodia formation. Increased invadopodia occurred at the expense of focal adhesion formation, resulting in a switch to increased tumor cell invasion through three-dimensional extracellular matrix. β2-adrenoceptor signaling increased invasion of tumor cells from explanted primary tumors through surrounding extracellular matrix, suggesting a possible mechanism for the observed increased spontaneous tumor cell dissemination in vivo. Selective antagonism of β2-adrenoceptors blocked invadopodia formation, suggesting a pharmacological strategy to prevent tumor cell dissemination.
  
  
  CONCLUSIONS
  These findings provide insight into conditions that control tumor cell invasion by identifying signaling through β2-adrenoceptors as a regulator of invadopodia formation. These findings suggest novel pharmacological strategies for intervention, by using β-blockers to target β2-adrenoceptors to limit tumor cell dissemination and metastasis.
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. sjcreed@hotmail.com.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Creed
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. caroline.le@monash.edu.
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Le
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Mhas4@student.monash.edu.
authors.forename: Mona
authors.initials: M
authors.lastname: Hassan
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. cindy.pon@monash.edu.
authors.forename: Cindy K
authors.initials: CK
authors.lastname: Pon
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. sabine.albold@monash.edu.
authors.forename: Sabine
authors.initials: S
authors.lastname: Albold
authors.affiliation: Department of Cell & Developmental Biology and Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA. keefe.chan@petermac.org.|Current address: Peter MacCallum Cancer Centre, East Melbourne, VIC, 3002, Australia. keefe.chan@petermac.org.
authors.forename: Keefe T
authors.initials: KT
authors.lastname: Chan
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA. Matthew.berginski@gmail.com.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Berginski
authors.affiliation: Department of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, 3010, Australia. zhuan@student.unimelb.edu.au.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Cell & Developmental Biology and Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA. jbear@email.unc.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. rob.lane@monash.edu.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. michelle.halls@monash.edu.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Halls
authors.affiliation: Department of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, 3010, Australia. dferrari@unimelb.edu.au.
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Cameron.nowell@monash.edu.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. erica.sloan@monash.edu.|Cousins Center for PNI, UCLA Semel Institute, and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA. erica.sloan@monash.edu.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, VIC, 3002, Australia. erica.sloan@monash.edu.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Sloan
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000378:metabolism*; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2