A role for PVRL4-driven cell-cell interactions in tumorigenesis

Elife. 2013 Apr 30;2:e00358. doi: 10.7554/eLife.00358.

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.

Keywords: Human; Mouse; anchorage-independence; genetic screen; transformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Adhesion
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / metabolism*
  • Cell Communication* / drug effects
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • DNA Copy Number Variations
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Integrin beta4 / metabolism
  • Mice, Nude
  • Nectins
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Tumor Burden
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / metabolism

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Cell Adhesion Molecules
  • ITGB4 protein, human
  • Integrin beta4
  • LNIR protein, human
  • Nectins
  • src-Family Kinases