Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 542, pages 246–250 (2017)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sas is required for normal cells to eliminate polarity-deficient neighbours.
Figure 2: Sas accumulates at the interface between normal and polarity-deficient cells.
Figure 3: PTP10D is required for polarity-deficient cells to be eliminated by normal cells.
Figure 4: Sas–PTP10D drives elimination of polarity-deficient cells by switching JNK signalling from pro-growth to pro-apoptotic.

Similar content being viewed by others

References

  1. 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)

    Article  CAS  Google Scholar 

  2. 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)

    Article  CAS  Google Scholar 

  3. Ohsawa, S. et al. Elimination of oncogenic neighbors by JNK-mediated engulfment in Drosophila. Dev. Cell 20, 315–328 (2011)

    Article  CAS  Google Scholar 

  4. Amoyel, M. & Bach, E. A. Cell competition: how to eliminate your neighbours. Development 141, 988–1000 (2014)

    Article  CAS  Google Scholar 

  5. Andersen, D. S. et al. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature 522, 482–486 (2015)

    Article  CAS  ADS  Google Scholar 

  6. Hogan, C. et al. Characterization of the interface between normal and transformed epithelial cells. Nat. Cell Biol. 11, 460–467 (2009)

    Article  CAS  Google Scholar 

  7. 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)

    Article  CAS  Google Scholar 

  8. Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975)

    Article  CAS  Google Scholar 

  9. Xu, T. & Rubin, G. M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237 (1993)

    Article  CAS  Google Scholar 

  10. 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)

    Article  CAS  Google Scholar 

  11. 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)

    Article  CAS  Google Scholar 

  12. Thompson, B. J. et al. Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev. Cell 9, 711–720 (2005)

    Article  CAS  Google Scholar 

  13. 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)

    Article  CAS  Google Scholar 

  14. 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)

    Article  CAS  Google Scholar 

  15. 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)

    Article  CAS  Google Scholar 

  16. 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)

    Article  CAS  Google Scholar 

  17. Jeon, M. & Zinn, K. Receptor tyrosine phosphatases control tracheal tube geometries through negative regulation of Egfr signaling. Development 136, 3121–3129 (2009)

    Article  CAS  Google Scholar 

  18. 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)

    Article  CAS  Google Scholar 

  19. Tarcic, G. et al. An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis. Curr. Biol. 19, 1788–1798 (2009)

    Article  CAS  Google Scholar 

  20. Tseng, A. S. et al. Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/Ras signaling pathway. Curr. Biol. 17, 728–733 (2007)

    Article  CAS  Google Scholar 

  21. Ohsawa, S. et al. Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490, 547–551 (2012)

    Article  CAS  ADS  Google Scholar 

  22. Pan, D. The Hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010)

    Article  CAS  Google Scholar 

  23. Tamori, Y. et al. Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol. 8, e1000422 (2010)

    Article  Google Scholar 

  24. 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)

    Article  CAS  Google Scholar 

  25. Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell 117, 117–129 (2004)

    Article  CAS  Google Scholar 

  26. Tyler, D. M., Li, W., Zhuo, N., Pellock, B. & Baker, N. E. Genes affecting cell competition in Drosophila. Genetics 175, 643–657 (2007)

    Article  CAS  Google Scholar 

  27. 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)

    Article  CAS  Google Scholar 

  28. Takahashi, K. et al. Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc. Natl Acad. Sci. USA 109, 1985–1990 (2012)

    Article  CAS  ADS  Google Scholar 

  29. 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)

    Article  CAS  Google Scholar 

  30. Norman, M. et al. Loss of Scribble causes cell competition in mammalian cells. J. Cell Sci. 125, 59–66 (2012)

    Article  CAS  Google Scholar 

  31. Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22, 451–461 (1999)

    Article  CAS  Google Scholar 

  32. Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000)

    Article  CAS  ADS  Google Scholar 

  33. 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)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Masatoshi Yamamoto and Shizue Ohsawa: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, 606-8501, Kyoto, Japan

    Masatoshi Yamamoto, Shizue Ohsawa, Kei Kunimasa & Tatsushi Igaki

  2. PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan

    Tatsushi Igaki

Authors
  1. Masatoshi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shizue Ohsawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kei Kunimasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatsushi Igaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.I. designed the screen; S.O. and K.K. conducted the screen; M.Y., S.O., K.K. and T.I. designed subsequent experiments; M.Y., S.O. and K.K. performed all experiments; M.Y., S.O., K.K. and T.I. analysed the data; and M.Y., S.O. and T.I. wrote the manuscript.

Corresponding author

Correspondence to Tatsushi Igaki.

Additional information

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

Extended Data Figure 1 Sas is required for normal cells to eliminate polarity-deficient neighbours.

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.

Extended Data Figure 2 Sas accumulates at the interface between normal and dlg−/− cells.

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).

Extended Data Figure 4 Sas and PTP10D are localized adjacent to each other in neighbouring cells.

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.

Extended Data Figure 9 scrib clones surrounded by sas clones activate EGFR–Ras signalling and Yki.

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).

Supplementary information

Supplementary Information

This file contains a list of detailed genotypes. (PDF 162 kb)

PowerPoint slides

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature21033

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer