title: Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior.
abstract: Commonly upregulated in human cancers, the scaffolding protein NEDD9/HEF1 is a known regulator of mesenchymal migration and cancer cell plasticity. However, the functional role of NEDD9 as a regulator of different migration/invasion modes in the context of breast cancer metastasis is currently unknown. Here, it is reported that NEDD9 is necessary for both mesenchymal and amoeboid individual cell migration/invasion in triple-negative breast cancer (TNBC). NEDD9 deficiency results in acquisition of the amoeboid morphology, but severely limits all types of cell motility. Mechanistically, NEDD9 promotes mesenchymal migration via VAV2-dependent Rac1 activation, and depletion of VAV2 impairs the ability of NEDD9 to activate Rac1. In addition, NEDD9 supports a mesenchymal phenotype through stimulating polymerization of actin via promoting CTTN phosphorylation in an AURKA-dependent manner. Interestingly, an increase in RhoA activity in NEDD9-depleted cells does not facilitate a switch to functional amoeboid motility, indicating a role of NEDD9 in the regulation of downstream RhoA signaling effectors. Simultaneous depletion of NEDD9 or inhibition of AURKA in combination with inhibition of the amoeboid driver ROCK results in an additional decrease in cancer cell migration/invasion. Finally, we confirmed that a dual targeting strategy is a viable and efficient therapeutic approach to hinder the metastasis of breast cancer in xenograft models, showcasing the important need for further clinical evaluation of this regimen to impede the spread of disease and improve patient survival.Implications:This study provides new insight into the therapeutic benefit of combining NEDD9 depletion with ROCK inhibition to reduce tumor cell dissemination and discovers a new regulatory role of NEDD9 in the modulation of VAV2-dependent activation of Rac1 and actin polymerization.Mol Cancer Res; 15(6); 670-82. ©2017 AACR.
authors.affiliation: Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Brandon C
authors.initials: BC
authors.lastname: Jones
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Kelley
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Yuriy V
authors.initials: YV
authors.lastname: Loskutov
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Marinak
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Varvara K
authors.initials: VK
authors.lastname: Kozyreva
authors.affiliation: Department of Pathology, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Smolkin
authors.affiliation: Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia. epugacheva@hsc.wvu.edu.|West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pugacheva
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D016688:Mice, Inbred NOD; D058990:Molecular Targeted Therapy / Q000379:methods*; D018994:Myosin Light Chains / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; D001381:Azepines; C495868:CTTN protein, human; D051356:Cortactin; D004791:Enzyme Inhibitors; C550258:MLN 8237; D018994:Myosin Light Chains; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D051567:Proto-Oncogene Proteins c-vav; D011725:Pyridines; D011743:Pyrimidines; C107953:RAC1 protein, human; C093651:VAV2 protein, human; C108830:Y 27632; C576917:AURKA protein, human; D064096:Aurora Kinase A; D054460:rho-Associated Kinases; D020830:rac1 GTP-Binding Protein