Credit: CORBIS

Multiple observations suggest that host tissues possess intrinsic tumour-suppressive activity that can eliminate premalignant cells (a type of cell competition). However, the mechanisms by which this occurs are unknown. Igaki and colleagues now show that Jun N-terminal kinase (JNK)-mediated engulfment of premalignant cells, by their surrounding wild-type neighbours, may be one such mechanism.

In Drosophila melanogaster imaginal epithelia, clones of cells in which the tumour suppressor genes scribble (scrib) or discs large (dlg) are mutated are outcompeted by surrounding wild-type cells and undergo JNK-dependent cell death. Using D. melanogaster eye-antennal discs, Ohsawa et al. analysed wild-type cells juxtaposed to scrib- or dlg-mutant clones to study the mechanisms of this tumour-suppressive activity. They found evidence of activated JNK signalling not only in mutant clones, but also in the wild-type neighbours. However, unlike JNK activation in mutant clones, JNK activation in surrounding wild-type cells was non-apoptotic. Intriguingly, blocking JNK signalling in the surrounding cells, by RNA interference or expression of a dominant-negative mutant of the Jun kinase Basket (BSKDN), suppressed elimination of scrib-mutant clones. The authors hypothesized that the cell surface tumour necrosis factor ligand Eiger, which was previously shown to activate JNK within scrib- and dlg-mutant clones, could also be upstream of JNK activation in wild-type neighbours. Indeed, overexpression of eiger in surrounding wild-type cells enhanced elimination of scrib-mutant clones. Together, these results indicate that Eiger–JNK signalling in normal cells promotes the elimination of neighbouring premalignant cells.

host tissues possess intrinsic tumour-suppressive activity that can eliminate premalignant cells

Next, Ohsawa et al. sought to identify effectors downstream of Eiger–JNK signalling. Guided by a candidate screen for proteins that regulate the actin cytoskeleton, a known outcome of JNK signalling, the authors found that PDGF- and VEGF-receptor related (PVR) is upregulated in both mutant clones and the surrounding wild-type cells, in a pattern similar to JNK activation. Knockdown of pvr in surrounding wild-type cells suppressed the elimination of scrib clones. Moreover, pvr knockdown in surrounding cells that overexpressed eiger prevented their ability to outcompete scrib clones, thereby placing PVR downstream of Eiger–JNK signalling.

How does Eiger–JNK–PVR signalling in wild-type cells lead to the elimination of premalignant neighbours? Live imaging of imaginal discs revealed that scrib-mutant cells are engulfed by their wild-type neighbours. Overexpression of eiger or pvr in surrounding wild-type cells enhanced the engulfment of scrib-mutant clones, whereas this was reduced in eiger-mutant discs. Finally, the authors showed that knockdown of engulfment and cell mobility (elmo) in surrounding wild-type cells suppressed the elimination of scrib-mutant clones, thereby implicating the ELMO–myoblast city (MBC) pathway, which mediates cytoskeletal rearrangement during phagocytosis, in this phenomenon.

These results show that activation of Eiger–JNK–PVR signalling in surrounding wild-type cells promotes ELMO–MBC-mediated engulfment of premalignant neighbours. It will be interesting to determine whether JNK-mediated cell engulfment is an evolutionarily conserved form of cell competition that eliminates premalignant cells from epithelia.