Elimination of Oncogenic Neighbors by JNK-Mediated Engulfment in Drosophila

SummaryA 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (181 K)Download as PowerPoint slideHighlights► Epithelial cells activate JNK in response to the emergence of oncogenic neighbors ► JNK activation promotes elimination of oncogenic polarity-deficient neighbors ► JNK activation drives overexpression of the PDGF/VEGF receptor, PVR ► Epithelial cells eliminate oncogenic neighbors by PVR-ELMO/Mbc-mediated engulfment