title: To "grow" or "go": TMEM16A expression as a switch between tumor growth and metastasis in SCCHN.
abstract: OBJECTIVE
  Tumor metastasis is the leading cause of death in patients with cancer. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key factor shifting tumors between growth and metastasis.
  
  
  METHODS
  We evaluated 26 pairs of primary and metastatic lymph node (LN) tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. In addition, we identified mechanisms by which TMEM16A expression influences tumor cell motility via proteomic screens of cell lines and in vivo mouse studies of metastasis.
  
  
  RESULTS
  Compared with primary tumors, TMEM16A expression decreases in metastatic LNs of patients with SCCHN. Stable reduction of TMEM16A expression enhances cell motility and increases metastases while decreasing tumor proliferation in an orthotopic mouse model. Evaluation of human tumor tissues suggests an epigenetic mechanism for decreasing TMEM16A expression through promoter methylation that correlated with a transition between an epithelial and a mesenchymal phenotype. These effects of TMEM16A expression on tumor cell size and epithelial-to-mesenchymal transition (EMT) required the amino acid residue serine 970 (S970); however, mutation of S970 to alanine does not disrupt the proliferative advantages of TMEM16A overexpression. Furthermore, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT.
  
  
  CONCLUSIONS
  Together, our results identify TMEM16A, an eight transmembrane domain Ca2+-activated Cl- channel, as a primary driver of the "Grow" or "Go" model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation.
authors.affiliation: VA Pittsburgh Health System, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Shiwarski
authors.affiliation: Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institute for Biomedical Research Inc., Cambridge, Massachusetts.
authors.forename: Anke
authors.initials: A
authors.lastname: Bill
authors.affiliation: VA Pittsburgh Health System, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jean
authors.initials: J
authors.lastname: Kim
authors.affiliation: VA Pittsburgh Health System, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Departments of Cell Biology and.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Bertrand
authors.affiliation: Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Raja S
authors.initials: RS
authors.lastname: Seethala
authors.affiliation: Yokohama City University, School of Medicine, Yokohama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sano
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffery N
authors.initials: JN
authors.lastname: Myers
authors.affiliation: Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ha
authors.affiliation: VA Pittsburgh Health System, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grandis
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institute for Biomedical Research Inc., Cambridge, Massachusetts.
authors.forename: L Alex
authors.initials: LA
authors.lastname: Gaither
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania.
authors.forename: Manojkumar A
authors.initials: MA
authors.lastname: Puthenveedu
authors.affiliation: VA Pittsburgh Health System, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. duvvuriu@upmc.edu.
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D063646:Carcinogenesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D018118:Chloride Channels / Q000096:biosynthesis* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C071776:radixin