The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition

Wild-type Drosophila epithelial cells outcompete proto-oncogenic cells through translocation of the ligand Sas to the wild-type–tumour cell interface, where it binds the PTP10D receptor of the tumour cell, initiating pro-apoptotic signalling. Sas and its receptor trigger anti-tumour response In the fruitfly Drosophila , cells that undergo oncogenic loss of polarity can be eliminated by surrounding polarized cells in a JNK-dependent mechanism. This report sheds light on how normal epithelium recognizes oncogenic cells in its midst and targets them for elimination. The authors propose that relocalization of the Sas–PTP10D ligand–receptor pair triggers its transactivation, restraining EGFR signalling and unleashing the pro-apopotic effects of JNK signalling. Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells 1 , 2 , 3 , 4 , 5 . Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination 1 , 2 , 3 , 4 , 5 , the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand–receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type ‘winner’ and the polarity-deficient ‘loser’ clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans -activation of Sas–PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas–PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.