Elimination of Oncogenic Neighbors by JNK-mediated Engulfment in Drosophila

Dev Cell. 2011 Mar 15;20(3):315-28. doi: 10.1016/j.devcel.2011.02.007.

Abstract

A newly emerged oncogenic cell in the epithelial population has to confront antitumor selective pressures in the host tissue. However, the mechanisms by which surrounding normal tissue exerts antitumor effects against oncogenically transformed cells are poorly understood. In Drosophila imaginal epithelia, clones of cells mutant for evolutionarily conserved tumor suppressor genes such as scrib or dlg lose their epithelial integrity and are eliminated from epithelia when surrounded by wild-type tissue. Here, we show that surrounding normal cells activate nonapoptotic JNK signaling in response to the emergence of oncogenic mutant cells. This JNK activation leads to upregulation of PVR, the Drosophila PDGF/VEGF receptor. Genetic and time-lapse imaging analyses reveal that PVR expression in surrounding cells activates the ELMO/Mbc-mediated phagocytic pathway, thereby eliminating oncogenic neighbors by engulfment. Our data indicate that JNK-mediated cell engulfment could be an evolutionarily conserved intrinsic tumor-suppression mechanism that eliminates premalignant cells from epithelia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / anatomy & histology*
  • Drosophila melanogaster / embryology*
  • Drosophila melanogaster / metabolism
  • Enzyme Activation
  • Epithelium / embryology
  • Epithelium / metabolism
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Neoplasms / pathology
  • Neoplasms / physiopathology
  • Oncogenes*
  • Phagocytosis / physiology*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Ced-12 protein, Drosophila
  • Drosophila Proteins
  • Membrane Proteins
  • Recombinant Fusion Proteins
  • Scrib protein, Drosophila
  • Tumor Suppressor Proteins
  • egr protein, Drosophila
  • Pvr protein, Drosophila
  • Receptor Protein-Tyrosine Kinases
  • JNK Mitogen-Activated Protein Kinases