title: A role for PVRL4-driven cell-cell interactions in tumorigenesis.
abstract: During all stages of tumor progression, cancer cells are subjected to inappropriate extracellular matrix environments and must undergo adaptive changes in order to evade growth constraints associated with the loss of matrix attachment. A gain of function screen for genes that enable proliferation independently of matrix anchorage identified a cell adhesion molecule PVRL4 (poliovirus-receptor-like 4), also known as Nectin-4. PVRL4 promotes anchorage-independence by driving cell-to-cell attachment and matrix-independent integrin β4/SHP-2/c-Src activation. Solid tumors frequently have copy number gains of the PVRL4 locus and some have focal amplifications. We demonstrate that the transformation of breast cancer cells is dependent on PVRL4. Furthermore, growth of orthotopically implanted tumors in vivo is inhibited by blocking PVRL4-driven cell-to-cell attachment with monoclonal antibodies, demonstrating a novel strategy for targeted therapy of cancer. DOI:http://dx.doi.org/10.7554/eLife.00358.001.
authors.affiliation: Department of Genetics , Harvard Medical School , Boston , United States ; Division of Genetics , Howard Hughes Medical Institute, Brigham and Women's Hospital , Boston , United States.
authors.forename: Natalya N
authors.initials: NN
authors.lastname: Pavlova
authors.forename: Christian
authors.initials: C
authors.lastname: Pallasch
authors.forename: Andrew E H
authors.initials: AE
authors.lastname: Elia
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Braun
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
authors.forename: Michael
authors.initials: M
authors.lastname: Hemann
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D039663:Integrin beta4 / Q000378:metabolism; D008819:Mice, Nude; D000075983:Nectins; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C059834:ITGB4 protein, human; D039663:Integrin beta4; D000075983:Nectins; C442228:NECTIN4 protein, human; D019061:src-Family Kinases
keywords: Human; Mouse; anchorage-independence; genetic screen; transformation