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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Brumby, A. M. & Richardson, H. E. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779 (2003)
Igaki, T., Pastor-Pareja, J. C., Aonuma, H., Miura, M. & Xu, T. Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev. Cell 16, 458–465 (2009)
Ohsawa, S. et al. Elimination of oncogenic neighbors by JNK-mediated engulfment in Drosophila. Dev. Cell 20, 315–328 (2011)
Amoyel, M. & Bach, E. A. Cell competition: how to eliminate your neighbours. Development 141, 988–1000 (2014)
Andersen, D. S. et al. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature 522, 482–486 (2015)
Hogan, C. et al. Characterization of the interface between normal and transformed epithelial cells. Nat. Cell Biol. 11, 460–467 (2009)
Kajita, M. et al. Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells. J. Cell Sci. 123, 171–180 (2010)
Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975)
Xu, T. & Rubin, G. M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237 (1993)
Schonbaum, C. P., Organ, E. L., Qu, S. & Cavener, D. R. The Drosophila melanogaster stranded at second (sas) gene encodes a putative epidermal cell surface receptor required for larval development. Dev. Biol. 151, 431–445 (1992)
Lee, H. K., Cording, A., Vielmetter, J. & Zinn, K. Interactions between a receptor tyrosine phosphatase and a cell surface ligand regulate axon guidance and glial-neuronal communication. Neuron 78, 813–826 (2013)
Thompson, B. J. et al. Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev. Cell 9, 711–720 (2005)
Moberg, K. H., Schelble, S., Burdick, S. K. & Hariharan, I. K. Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev. Cell 9, 699–710 (2005)
Ballesteros-Arias, L., Saavedra, V. & Morata, G. Cell competition may function either as tumour-suppressing or as tumour-stimulating factor in Drosophila. Oncogene 33, 4377–4384 (2014)
Uhlirova, M. & Bohmann, D. JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 25, 5294–5304 (2006)
Enomoto, M., Kizawa, D., Ohsawa, S. & Igaki, T. JNK signaling is converted from anti- to pro-tumor pathway by Ras-mediated switch of Warts activity. Dev. Biol. 403, 162–171 (2015)
Jeon, M. & Zinn, K. Receptor tyrosine phosphatases control tracheal tube geometries through negative regulation of Egfr signaling. Development 136, 3121–3129 (2009)
Jeon, M. & Zinn, K. R3 receptor tyrosine phosphatases: conserved regulators of receptor tyrosine kinase signaling and tubular organ development. Semin. Cell Dev. Biol. 37, 119–126 (2015)
Tarcic, G. et al. An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis. Curr. Biol. 19, 1788–1798 (2009)
Tseng, A. S. et al. Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/Ras signaling pathway. Curr. Biol. 17, 728–733 (2007)
Ohsawa, S. et al. Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490, 547–551 (2012)
Pan, D. The Hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010)
Tamori, Y. et al. Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol. 8, e1000422 (2010)
de la Cova, C., Abril, M., Bellosta, P., Gallant, P. & Johnston, L. A. Drosophila Myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004)
Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell 117, 117–129 (2004)
Tyler, D. M., Li, W., Zhuo, N., Pellock, B. & Baker, N. E. Genes affecting cell competition in Drosophila. Genetics 175, 643–657 (2007)
Hendriks, W. J. A. J. & Pulido, R. Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities. Biochim. Biophys. Acta 1832, 1673–1696 (2013)
Takahashi, K. et al. Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc. Natl Acad. Sci. USA 109, 1985–1990 (2012)
Whiteford, J. R. et al. Syndecan-2 is a novel ligand for the protein tyrosine phosphatase receptor CD148. Mol. Biol. Cell 22, 3609–3624 (2011)
Norman, M. et al. Loss of Scribble causes cell competition in mammalian cells. J. Cell Sci. 125, 59–66 (2012)
Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22, 451–461 (1999)
Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000)
Goode, S. & Perrimon, N. Inhibition of patterned cell shape change and cell invasion by Discs large during Drosophila oogenesis. Genes Dev. 11, 2532–2544 (1997)
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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