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Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis

Nature Cell Biology volume 18, pages 100–110 (2016)Cite this article

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Abstract

Aneuploidy is found in most solid tumours, but it remains unclear whether it is the cause or the consequence of tumorigenesis. Using Plk4 overexpression (PLK4OE) during epidermal development, we assess the impact of centrosome amplification and aneuploidy on skin development and tumorigenesis. PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, leading to p53 stabilization and apoptosis of epidermal progenitors. The resulting delayed epidermal stratification led to skin barrier defects. Plk4 transgene expression was shut down postnatally in the surviving mice and PLK4OE mice never developed skin tumours. Concomitant PLK4OE and p53 deletion (PLK4OE/p53cKO) rescued the differentiation defects, but did not prevent the apoptosis of PLK4OE cells. Remarkably, the short-term presence of cells with supernumerary centrosomes in PLK4OE/p53cKO mice was sufficient to generate aneuploidy in the adult epidermis and triggered spontaneous skin cancers with complete penetrance. These results reveal that aneuploidy induced by transient centrosome amplification can accelerate tumorigenesis in p53-deficient cells.

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Figure 1: PLK4 overexpression impairs skin stratification.
Figure 2: PLK4 overexpression induced epidermal progenitor apoptosis.
Figure 3: p53 deletion rescues the defect of skin stratification in PLK4OE mice.
Figure 4: PLK4 overexpression induced p53-dependent and-independent apoptosis.
Figure 5: PLK4 overexpression causes aneuploidy only in p53-deficient progenitors.
Figure 6: PLK4OE in p53-deficient progenitors accelerates skin tumour formation.
Figure 7: Model of skin tumorigenesis mediated by PLK4OE in p53-deficient epidermis.

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  • 10 December 2015

    In the version of this Article originally published online, Bram Boeckx and Diether Lambrechts should have had a second affiliation: Vesalius Research Center, VIB, 3000 Leuven, Belgium. This is now correct in all versions of the Article.

References

  1. Nigg, E. A. & Raff, J. W. Centrioles, centrosomes, and cilia in health and disease. Cell 139, 663–678 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Bettencourt-Dias, M., Hildebrandt, F., Pellman, D., Woods, G. & Godinho, S. A. Centrosomes and cilia in human disease. Trends Genet. 27, 307–315 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Firat-Karalar, E. N. & Stearns, T. The centriole duplication cycle. Phil. Trans. R. Soc. 369, 20130460 (2014).

    Article  Google Scholar 

  4. Anderhub, S. J., Kramer, A. & Maier, B. Centrosome amplification in tumorigenesis. Cancer Lett. 322, 8–17 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Boveri, T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J. Cell Sci. 121, 1–84 (2008).

    Article  PubMed  Google Scholar 

  6. Lingle, W. L. et al. Centrosome amplification drives chromosomal instability in breast tumor development. Proc. Natl Acad. Sci. USA 99, 1978–1983 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pihan, G. A., Wallace, J., Zhou, Y. & Doxsey, S. J. Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res. 63, 1398–1404 (2003).

    CAS  PubMed  Google Scholar 

  8. Holland, A. J. & Cleveland, D. W. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat. Rev. Mol. Cell Biol. 10, 478–487 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Weaver, B. A. & Cleveland, D. W. Does aneuploidy cause cancer? Curr. Opin. Cell Biol. 18, 658–667 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Foijer, F. et al. Spindle checkpoint deficiency is tolerated by murine epidermal cells but not hair follicle stem cells. Proc. Natl Acad. Sci. USA 110, 2928–2933 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Torchia, E. C., Zhang, L., Huebner, A. J., Sen, S. & Roop, D. R. Aurora kinase-A deficiency during skin development impairs cell division and stratification. J. Invest. Dermatol. 133, 78–86 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Solomon, D. A. et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333, 1039–1043 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ricke, R. M., Jeganathan, K. B. & van Deursen, J. M. Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J. Cell Biol. 193, 1049–1064 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rao, C. V. et al. Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc. Natl Acad. Sci. USA 102, 4365–4370 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Weaver, B. A., Silk, A. D., Montagna, C., Verdier-Pinard, P. & Cleveland, D. W. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25–36 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Chesnokova, V., Kovacs, K., Castro, A. V., Zonis, S. & Melmed, S. Pituitary hypoplasia in Pttg-/- mice is protective for Rb+/- pituitary tumorigenesis. Mol. Endocrinol. 19, 2371–2379 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Sussan, T. E., Yang, A., Li, F., Ostrowski, M. C. & Reeves, R. H. Trisomy represses Apc(Min)-mediated tumours in mouse models of Down’s syndrome. Nature 451, 73–75 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Zyss, D. & Gergely, F. Centrosome function in cancer: guilty or innocent? Trends Cell Biol. 19, 334–346 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Basto, R. et al. Centrosome amplification can initiate tumorigenesis in flies. Cell 133, 1032–1042 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sabino, D. et al. Moesin is a major regulator of centrosome behavior in epithelial cells with extra centrosomes. Curr. Biol. 25, 879–889 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Marthiens, V. et al. Centrosome amplification causes microcephaly. Nat. Cell Biol. 15, 731–740 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Perez-Losada, J. & Balmain, A. Stem-cell hierarchy in skin cancer. Nat. Rev. Cancer 3, 434–443 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Boukamp, P. Non-melanoma skin cancer: what drives tumor development and progression? Carcinogenesis 26, 1657–1667 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Nassar, D., Latil, M., Boeckx, B., Lambrechts, D. & Blanpain, C. Genomic landscape of carcinogen and genetically-induced mouse skin squamous cell carcinoma. Nat. Med. 8, 946–954 (2015).

    Article  Google Scholar 

  25. McGranahan, N., Burrell, R. A., Endesfelder, D., Novelli, M. R. & Swanton, C. Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep. 13, 528–538 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Vasioukhin, V., Degenstein, L., Wise, B. & Fuchs, E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl Acad. Sci. USA 96, 8551–8556 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sotiropoulou, P. A. & Blanpain, C. Development and homeostasis of the skin epidermis. Cold Spring Harb. Perspect. Biol. 4, a008383 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kleylein-Sohn, J. et al. Plk4-induced centriole biogenesis in human cells. Dev. Cell 13, 190–202 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Holland, A. J. et al. The autoregulated instability of Polo-like kinase 4 limits centrosome duplication to once per cell cycle. Genes Dev. 26, 2684–2689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Blanpain, C., Lowry, W. E., Pasolli, H. A. & Fuchs, E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev. 20, 3022–3035 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Koster, M. I. & Roop, D. R. Mechanisms regulating epithelial stratification. Annu. Rev. Cell Dev. Biol. 23, 93–113 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Sancar, A., Lindsey-Boltz, L. A., Unsal-Kacmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Sotiropoulou, P. A. et al. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat. Cell Biol. 12, 572–582 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Williams, S. E., Ratliff, L. A., Postiglione, M. P., Knoblich, J. A. & Fuchs, E. Par3-mInsc and Galphai3 cooperate to promote oriented epidermal cell divisions through LGN. Nat. Cell Biol. 16, 758–769 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Izumi, H. & Kaneko, Y. Evidence of asymmetric cell division and centrosome inheritance in human neuroblastoma cells. Proc. Natl Acad. Sci. USA 109, 18048–18053 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu, X. et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl Acad. Sci. USA 104, 12111–12116 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Holland, A. J., Lan, W., Niessen, S., Hoover, H. & Cleveland, D. W. Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability. J. Cell Biol. 188, 191–198 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ziegler, A. et al. Sunburn and p53 in the onset of skin cancer. Nature 372, 773–776 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Berg, R. J. et al. Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells. Proc. Natl Acad. Sci. USA 93, 274–278 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ruggeri, B. et al. Alterations of the p53 tumor suppressor gene during mouse skin tumor progression. Cancer Res. 51, 6615–6621 (1991).

    CAS  PubMed  Google Scholar 

  42. Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29, 418–425 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Sotiropoulou, P. A. et al. BRCA1 deficiency in skin epidermis leads to selective loss of hair follicle stem cells and their progeny. Genes Dev. 27, 39–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

C.B. is an investigator of WELBIO; Ö.S. is supported by a TELEVIE fellowship. This work was supported by the FNRS, TELEVIE, the PAI programme, a research grant from the Fondation contre le Cancer, the ULB Fondation, the foundation Bettencourt Schueller, the foundation Baillet Latour, a grant from the European Research Council (ERC) and a grant from AICR now worldwide cancer research (13-0170) to V.M. and R.B.

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Authors and Affiliations

  1. Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium

    Özdemirhan Serçin, Jean-Christophe Larsimont, Andrea E. Karambelas, Virginie Moers & Cédric Blanpain

  2. Institut Curie, Centre de Recherche, Paris F-75248, France

    Veronique Marthiens & Renata Basto

  3. Department of Oncology, Laboratory for Translational Genetics, KU Leuven 3000, Belgium

    Bram Boeckx & Diether Lambrechts

  4. Vesalius Research Center, VIB, 3000 Leuven, Belgium

    Bram Boeckx & Diether Lambrechts

  5. Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium

    Marie Le Mercier

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Contributions

Ö.S. and C.B. designed the experiments and performed data analysis; Ö.S. performed most of the experiments, J.-C.L. and A.E.K. conducted proliferation experiments; V.M. performed RNA purification; M.L.M. performed FISH experiments; D.L. and B.B. performed tumour sequencing and analysis. V.Ma. and R.B. generated the PLK4OE mice; Ö.S. and C.B. wrote the manuscript.

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Correspondence to Cédric Blanpain.

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Integrated supplementary information

Supplementary Figure 1 Schematic representation of transgene recombination.

(a) A loxp-STOP-loxp cassette prevents expression of mCherry-Plk4 construct. (b) Upon initiation of K14 expression in mouse skin epidermis, Cre accumulates and recombines loxP sites and enables Plk4 overexpression in mice older than E14. Unrecombined and recombined specific primers and PCR are detailed in Methods.

Supplementary Figure 2 mCherry-Plk4 localizes to centrosomes in mouse skin epidermis and causes centrosome supernumerary.

(a) Keratinocytes extracted from E16.5 embryos were stained for centrosome marker γ-tubulin. mCherry-Plk4 co-localizes with γ-tubulin, insets show higher magnification of the same image for co-localization. (b) Quantification of percentage of cells mCherry-positive and cells with >2 centrosomes. Data represent the mean of n = 3 mice. (≥30 cells per mouse were counted) Nuclei were stained with DAPI and white scale bars represent 5 μm. Source data are available in Supplementary Table 1.

Supplementary Figure 3 Plk4 overexpression causes skin development defects.

(a) Newborn PLK4OE mice show shiny skin and open eyes. (b) Close up image of (a) reveals incomplete eyelid formation in PLK4OE but not control mice. (c,d) Macroscopic image of newborn mice show that only PLK4OE but not control mice exhibit shiny face (c) and back skin (d).

Supplementary Figure 4 PCR of recombined and unrecombined Plk4 transgene.

(a) Recombination of the transgene was detected by genomic PCR only in double transgenic mouse at E16.5, P1, adult and in different tumours but not in control mice or CRE negative mice, non-recombined allele was detected by a primer designed specifically to amplify the cells which did not recombine the transgene. ß-actin was used as a loading control.

Supplementary Figure 5 Expression of mCherry-PLK4 mRNA is lost in adult mice.

(a) Expression of mCherry-Plk4 was tested by RT-PCR in P1 and adult mice. Only P1 but not adult PLK4OE and PLK4OE/p53cKO mice show amplification of the RT product. ß-actin was used as a loading control.

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Serçin, Ö., Larsimont, JC., Karambelas, A. et al. Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Nat Cell Biol 18, 100–110 (2016). https://doi.org/10.1038/ncb3270

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