title: NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis.
abstract: The scaffolding protein NEDD9 is an established prometastatic marker in several cancers. Nevertheless, the molecular mechanisms of NEDD9-driven metastasis in cancers remain ill-defined. Here, using a comprehensive breast cancer tissue microarray, it was shown that increased levels of NEDD9 protein significantly correlated with the transition from carcinoma in situ to invasive carcinoma. Similarly, it was shown that NEDD9 overexpression is a hallmark of highly invasive breast cancer cells. Moreover, NEDD9 expression is crucial for the protease-dependent mesenchymal invasion of cancer cells at the primary site but not at the metastatic site. Depletion of NEDD9 is sufficient to suppress invasion of tumor cells in vitro and in vivo, leading to decreased circulating tumor cells and lung metastases in xenograft models. Mechanistically, NEDD9 localized to invasive pseudopods and was required for local matrix degradation. Depletion of NEDD9 impaired invasion of cancer cells through inactivation of membrane-bound matrix metalloproteinase MMP14 by excess TIMP2 on the cell surface. Inactivation of MMP14 is accompanied by reduced collagenolytic activity of soluble metalloproteinases MMP2 and MMP9. Reexpression of NEDD9 is sufficient to restore the activity of MMP14 and the invasive properties of breast cancer cells in vitro and in vivo. Collectively, these findings uncover critical steps in NEDD9-dependent invasion of breast cancer cells.
  
  
  CONCLUSIONS
  This study provides a mechanistic basis for potential therapeutic interventions to prevent metastasis.
authors.affiliation: Department of Biochemistry and Mary Babb Randolph Cancer Center, PO Box 9142, 1 Medical Center Drive, West Virginia University School of Medicine, Morgantown, WV 26506. epugacheva@hsc.wvu.edu.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: McLaughlin
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Ice
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rajulapati
authors.forename: Polina Y
authors.initials: PY
authors.lastname: Kozyulina
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Livengood
authors.forename: Varvara K
authors.initials: VK
authors.lastname: Kozyreva
authors.forename: Yuriy V
authors.initials: YV
authors.lastname: Loskutov
authors.forename: Mark V
authors.initials: MV
authors.lastname: Culp
authors.forename: Scott A
authors.initials: SA
authors.lastname: Weed
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ivanov
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pugacheva
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D046888:Tissue Array Analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14