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 cells1,2,3,4,5. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination1,2,3,4,5, 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.
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We thank J. Vaughen for comments on the manuscript; Y. Matsumoto, T. Sawada, K. Takino, M. Katsukawa, and C. Iida for technical support; D. Cavener, I. Hariharan, and K. Irvine for antibodies; D. Bilder, S. Goode, T. Xu, K. Zinn, the Bloomington Drosophila Stock Center (Indiana, USA), the Vienna Drosophila Resource Center (Vienna, Austria), the NIG Stock Center (Mishima, Japan), and the Drosophila Genomics and Genetic Resources (Kyoto Stock Center, Japan) for fly stocks. This work was supported in part by grants from the MEXT/JSPS KAKENHI (grant number 26114002, 25112710, 15H05862, and 23127508) to S.O. and T.I., the Nakajima Foundation to S.O., the Inoue Science Research Award to S.O, the Naito Foundation to T.I, the Takeda Science Foundation to S.O. and T.I., and the JST to T.I. M.Y. was supported by the Platform for Dynamic Approaches to Living System from AMED.
Reviewer Information Nature thanks G. Morata, K. Zinn and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
a, A ‘non-autonomous’ genetic mosaic screen for mutants that fail to eliminate polarity-deficient cells from the eye imaginal epithelium. scrib−/− clones are normally eliminated by cell competition when surrounded by wild-type tissue. Using the genetic mosaic technique, EMS-induced mutations were introduced only in wild-type cells in scrib−/− mosaic eye discs (see Methods for details). The elimination-defective phenotype was assessed by red-pigmented clones or melanization generated in the adult eye. b, Mapping of a mutation causing the elimination-defective phenotype. Using a series of chromosomal deficiency fly lines, the responsible genomic region was narrowed down to 84C8–84D2 based on lethality with eld-4. c, Eye-antennal-disc-bearing GFP-labelled eld-4 clones immunostained for Sas and DAPI. d–g, Adult eyes of MARCM-induced mosaics of wt//wt (d), wt//dlg−/− (e), dlg−/−//sas-RNAi (f), and wt//sas-RNAi (g) clones. h–k, Eye discs of MARCM-induced mosaics of wt//wt (g), wt//dlg−/− (h), dlg−/−//sas-RNAi (i), and wt//sas-RNAi (j) clones. l, Quantification of relative size of clones in genotypes shown in h (n = 13, number of eye discs), i (n = 14), j (n = 13), k (n = 15). Error bars show s.d.; ns, not significant (P > 0.05); **P < 0.01 by Mann–Whitney U-test. Scale bars, 20 μm.
a, b, xy (upper panels) or xz (lower panels) confocal sections of eye disc bearing GFP-labelled wild-type (a) or dlg−/− (b) clones immunostained for Sas (a’, b’) and anti-PTP10D (a’’, b’’). Scale bars, 20 μm.
Extended Data Figure 3 In vivo RNAi screen to identify the Sas receptor required for elimination of polarity-deficient cells.
a, In vivo RNAi screen schematic for identifying the Sas receptor. As the VWC and FN3 domains of Sas can bind homophilically, RNAi against 32 Drosophila transmembrane proteins containing either VWC or FN3 domains was driven individually inside scrib−/− clones and assessed for overgrowth in adult eyes. b, c, Adult eyes of MARCM-induced GFP-labelled mosaics of scrib−/− clones (b, as a control) simultaneously expressing each candidate RNAi (c).
a, b, xz sections of the confocal image of GFP-labelled scrlb−/− mutant clones (a, cyan) or scrib−/− sas−/− double mutant clones (b, cyan) immunostained for PTP10D (green) and Sas (magenta). Fluorescent intensities of Sas and PTP10D are measured by imageJ software at the yellow lines (a’ and b’).
Extended Data Figure 5 Sas and PTP10D localize at the lateral interface between normal and neoplastic tumour-suppressor mutants but not non-oncogenic polarity mutants.
a–e, xz sections of the confocal image of GFP-labelled crb−/− (a), sdt−/− (b), RabDN (c), ept−/− (d), and vps25−/− (e) clones immunostained with anti-Sas (a’–e’), anti-PTP10D (a’’–e’’), and merged image (a’’’–e’’’) are shown.
Extended Data Figure 6 Sas–PTP10D drives elimination of polarity-deficient cells by modulating EGFR and Hippo signalling.
a–c, Eye disc bearing GFP-labelled scrib−/− (a), wild-type (b), or Egfr-RNAi (c) clones; d, Quantification of relative size of clones in genotypes shown in b (n = 15, number of eye discs), c (n = 12), i (n = 14), j (n = 14). Error bars show s.d.; ns, not significant (P > 0.05); *P < 0.05 by Mann–Whitney U-test. e, f, Eye disc bearing GFP-labelled scrib−/− (e) or scrib−/− and Ptp10D-RNAi (f) clones stained with phalloidin. g, Eye disc bearing GFP-labelled scrib−/− + Ptp10D-RNAi clones stained for Yki and with DAPI. h–j, Eye disc bearing GFP-labelled scrib−/− + Ptp10D-RNAi + yki-RNAi (h), yki-RNAi (i), or Wts-overexpressing (j) clones. Egfr-RNAi or yki-RNAi did not reduce clone size, perhaps owing to incomplete knockdown. Scale bars, 20 μm.
Extended Data Figure 7 EGFR and PTP10D relocalize from the apical to lateral cell surface at the boundary between scrib clones and wild-type clones.
a–d, xz section of the confocal image of GFP-labelled scrlb−/− clones (a) immunostained for EGFR (b), PTP10D (c), and merged image (d) are shown.
Extended Data Figure 8 Expression of EGFRCA or RasV12 abolishes scrib cell elimination while expression of RasDN in scrib + PTP10D-RNAi clones suppresses their growth.
a–c, Eye disc bearing GFP-labelled MARCM clones with scrib−/− + EGFRCA(a), scrib−/− + RasV12 (b), or scrib−/− + PTP10D-RNAi + UAS-RasDN (c) is shown.
a, b, Eye disc bearing GFP-labelled scrlb−/− clones surrounded by GFP-negative wild-type (a–a’’) or sas−/− eld-4 (b–b’’) clones stained with anti-Capicua. Arrows represent typical scrib mutant clones that downregulate Cic (b-b’’) or upregulate ex-lacZ (d-d’’) expression. c, d, Eye disc bearing GFP-labelled scrlb−/− clones surrounded by GFP-negative wild-type (c–c’’) or sas−/− eld-4 (d–d’’) clones immunostained for β-galactosidase to label the expanded (ex)–lacZ reporter. e, f, Eye disc bearing GFP-labelled scrlb−/− clones surrounded by GFP-negative wild-type (e–e’’) or sas−/− eld-4 (f–f’’) clones stained with anti-Yorkie (Yki).
Extended Data Figure 10 Apical and sub-apical proteins are localized at the lateral interface between wild-type and scrib−/− clones.
xz sections of the confocal image of GFP-labelled scrlb−/− clones immunostained for Baz (a), Patj (b), aPKC/Sas (c), and E-cadherin/Sas (d).
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Yamamoto, M., Ohsawa, S., Kunimasa, K. et al. The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 542, 246–250 (2017). https://doi.org/10.1038/nature21033
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