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Fusion-mediated chromosomal instability promotes aneuploidy patterns that resemble human tumors

Oncogene volume 38, pages 6083–6094 (2019)Cite this article

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Abstract

Oncogenesis is considered to result from chromosomal instability, in addition to oncogene and tumor-suppressor alterations. Intermediate to aneuploidy and chromosomal instability, genome doubling is a frequent event in tumor development but the mechanisms driving tetraploidization and its impact remain unexplored. Cell fusion, one of the pathways to tetraploidy, is a physiological process involved in mesenchymal cell differentiation. Besides simple genome doubling, cell fusion results in the merging of two different genomes that can be destabilized upon proliferation. By testing whether cell fusion is involved in mesenchymal oncogenesis, we provide evidence that it induces genomic instability and mediates tumor initiation. After a latency period, the tumor emerges with the cells most suited for its development. Furthermore, hybrid tumor genomes were stabilized after this selection process and were very close to those of human pleomorphic mesenchymal tumors. Thus genome restructuring triggered by cell fusion may account for the chromosomal instability involved in oncogenesis.

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References

  1. Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumour cells with defined genetic elements. Nature. 1999;400:464–8.

    Article  CAS  Google Scholar 

  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  3. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pan-cancer patterns of somatic copy-number alteration. Nat Genet. 2013;45:1134.

    Article  CAS  Google Scholar 

  4. Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ, et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell. 2013;155:948–62.

    Article  CAS  Google Scholar 

  5. Davoli T, de Lange T. The causes and consequences of polyploidy in normal development and cancer. Annu Rev Cell Dev Biol. 2011;27:585–610.

    Article  CAS  Google Scholar 

  6. Bielski CM, Zehir A, Penson AV, Donoghue MTA, Chatila W, Armenia J, et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat Genet. 2018;50:1189–95.

    Article  CAS  Google Scholar 

  7. Margolis RL. Tetraploidy and tumor development. Cancer Cell. 2005;8:353–4.

    Article  CAS  Google Scholar 

  8. Ganem NJ, Storchova Z, Pellman D. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev. 2007;17:157–62.

    Article  CAS  Google Scholar 

  9. Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M, et al. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev. 2008;22:2189–203.

    Article  CAS  Google Scholar 

  10. Vitale I, Galluzzi L, Castedo M, Kroemer G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol. 2011;12:385–92.

    Article  CAS  Google Scholar 

  11. Vitale I, Galluzzi L, Senovilla L, Criollo A, Jemaà M, Castedo M, et al. Illicit survival of cancer cells during polyploidization and depolyploidization. Cell Death Differ. 2011;18:1403–13.

    Article  CAS  Google Scholar 

  12. Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 2005;437:1043–7.

    Article  CAS  Google Scholar 

  13. Santaguida S, Amon A. Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat Rev Mol Cell Biol. 2015;16:473–85.

    Article  CAS  Google Scholar 

  14. Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science. 2017;355:eaaf8399.

    Article  Google Scholar 

  15. Turajlic S, Xu H, Litchfield K, Rowan A, Chambers T, Lopez JI, et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell. 2018;173:581–594.e12.

    Article  CAS  Google Scholar 

  16. Bakhoum SF, Ngo B, Laughney AM, Cavallo J-A, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018;553:467–72.

    Article  CAS  Google Scholar 

  17. Davoli T, Denchi EL, de Lange T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell. 2010;141:81–93.

    Article  CAS  Google Scholar 

  18. Targa A, Rancati G. Cancer: a CINful evolution. Curr Opin Cell Biol. 2018;52:136–44.

    Article  CAS  Google Scholar 

  19. Duelli D, Lazebnik Y. Cell fusion: a hidden enemy? Cancer Cell. 2003;3:445–8.

    Article  CAS  Google Scholar 

  20. Duelli D, Lazebnik Y. Cell-to-cell fusion as a link between viruses and cancer. Nat Rev Cancer. 2007;7:968–76.

    Article  CAS  Google Scholar 

  21. Duelli DM, Padilla-Nash HM, Berman D, Murphy KM, Ried T, Lazebnik Y. A virus causes cancer by inducing massive chromosomal instability through cell fusion. Curr Biol. 2007;17:431–7.

    Article  CAS  Google Scholar 

  22. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528–30.

    Article  CAS  Google Scholar 

  23. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002;416:542–5.

    Article  CAS  Google Scholar 

  24. Weimann JM, Johansson CB, Trejo A, Blau HM. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol. 2003;5:959–66.

    Article  CAS  Google Scholar 

  25. Rizvi AZ, Swain JR, Davies PS, Bailey AS, Decker AD, Willenbring H, et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci USA. 2006;103:6321–5.

    Article  CAS  Google Scholar 

  26. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003;425:968–73.

    Article  CAS  Google Scholar 

  27. Camargo FD, Green R, Capetanaki Y, Jackson KA, Goodell MA, Capetenaki Y. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med. 2003;9:1520–7.

    Article  CAS  Google Scholar 

  28. Johansson CB, Youssef S, Koleckar K, Holbrook C, Doyonnas R, Corbel SY, et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol. 2008;10:575–83.

    Article  CAS  Google Scholar 

  29. Nygren JM, Liuba K, Breitbach M, Stott S, Thorén L, Roell W, et al. Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nat Cell Biol. 2008;10:584–92.

    Article  CAS  Google Scholar 

  30. Zhou X, Merchak K, Lee W, Grande JP, Cascalho M, Platt JL. Cell Fusion Connects Oncogenesis with Tumor Evolution. Am J Pathol. 2015;185:2049–60.

    Article  CAS  Google Scholar 

  31. Aichel O. “Über Zellverschmelzung mit qualitativ abnormer chromosomenverteilung als ursache der geschwulstbildung” [About cell fusion with qualitatively abnormal. chromosome distribution as cause for tumor formation.]. In: Vorträge und aufsätze über entvickelungsmechanik der organismen. Leipzig: Wilhelm Engelmann; 1911. p. 92–111.

  32. Pawelek JM, Chakraborty AK. Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer. 2008;8:377–86.

    Article  CAS  Google Scholar 

  33. Pawelek JM. Tumour-cell fusion as a source of myeloid traits in cancer. Lancet Oncol. 2005;6:988–93.

    Article  CAS  Google Scholar 

  34. Powell AE, Anderson EC, Davies PS, Silk AD, Pelz C, Impey S, et al. Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res. 2011;71:1497–505.

    Article  CAS  Google Scholar 

  35. Gast CE, Silk AD, Zarour L, Riegler L, Burkhart JG, Gustafson KT, et al. Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival. Sci Adv. 2018;4:eaat7828.

    Article  Google Scholar 

  36. Chakraborty A, Lazova R, Davies S, Bäckvall H, Ponten F, Brash D, et al. Donor DNA in a renal cell carcinoma metastasis from a bone marrow transplant recipient. Bone Marrow Transplant. 2004;34:183–6.

    Article  CAS  Google Scholar 

  37. Clawson GA, Kimchi E, Patrick SD, Xin P, Harouaka R, Zheng S, et al. Circulating tumor cells in melanoma patients. PLoS ONE. 2012;7:e41052.

    Article  CAS  Google Scholar 

  38. Clawson GA. Cancer. Fusion for moving. Science. 2013;342:699–700.

    Article  CAS  Google Scholar 

  39. Clawson GA, Matters GL, Xin P, Imamura-Kawasawa Y, Du Z, Thiboutot DM, et al. Macrophage-tumor cell fusions from peripheral blood of melanoma patients. PLoS ONE. 2015;10:e0134320.

    Article  Google Scholar 

  40. Clawson GA, Matters GL, Xin P, McGovern C, Wafula E, dePamphilis C, et al. ‘Stealth dissemination’ of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma. PLoS ONE. 2017;12:e0184451.

    Article  Google Scholar 

  41. Lazova R, Laberge GS, Duvall E, Spoelstra N, Klump V, Sznol M, et al. A melanoma brain metastasis with a donor-patient hybrid genome following bone marrow transplantation: first evidence for fusion in human cancer. PLoS ONE. 2013;8:e66731.

    Article  CAS  Google Scholar 

  42. Kurgyis Z, Kemény LV, Buknicz T, Groma G, Oláh J, Jakab Á, et al. Melanoma-derived BRAF(V600E) mutation in peritumoral stromal cells: implications for in vivo cell fusion. Int J Mol Sci. 2016;17:E980.

    Article  Google Scholar 

  43. LaBerge GS, Duvall E, Grasmick Z, Haedicke K, Pawelek J. A melanoma lymph node metastasis with a donor-patient hybrid genome following bone marrow transplantation: a second case of leucocyte-tumor cell hybridization in cancer metastasis. PLoS ONE. 2017;12:e0168581.

    Article  Google Scholar 

  44. Luo F, Liu T, Wang J, Li J, Ma P, Ding H, et al. Bone marrow mesenchymal stem cells participate in prostate carcinogenesis and promote growth of prostate cancer by cell fusion in vivo. Oncotarget. 2016;7:30924–34.

  45. Li G, Kikuchi K, Radka M, Abraham J, Rubin BP, Keller C. IL-4 receptor blockade abrogates satellite cell: Rhabdomyosarcoma fusion and prevents tumor establishment. STEM Cells. 2013;31:2304–12.

    Article  CAS  Google Scholar 

  46. Mukhopadhyay KD, Bandyopadhyay A, Chang T-TA, Elkahloun AG, Cornell JE, Yang J, et al. Isolation and characterization of a metastatic hybrid cell line generated by ER negative and ER positive breast cancer cells in mouse bone marrow. PLoS ONE. 2011;6:e20473.

    Article  CAS  Google Scholar 

  47. Kemény LV, Kurgyis Z, Buknicz T, Groma G, Jakab Á, Zänker K, et al. Melanoma cells can adopt the phenotype of stromal fibroblasts and macrophages by spontaneous cell fusion in vitro. Int J Mol Sci. 2016;17:E826.

    Article  Google Scholar 

  48. Yano T, Tanaka M, Fukuda N, Ueda T, Nagase H. Loss of mutant mitochondrial DNA harboring the MELAS A3243G mutation in human cybrid cells after cell-cell fusion with normal tissue-derived fibroblast cells. Int J Mol Med. 2010;25:153–8.

    CAS  PubMed  Google Scholar 

  49. Durrieu-Gaillard S, Dumay-Odelot H, Boldina G, Tourasse NJ, Allard D, André F, et al. Regulation of RNA polymerase III transcription during transformation of human IMR90 fibroblasts with defined genetic elements. Cell Cycle. 2018;17:605–15.

    Article  CAS  Google Scholar 

  50. Chibon F, Mairal A, Fréneaux P, Terrier P, Coindre JM, Sastre X, et al. The RB1 gene is the target of chromosome 13 deletions in malignant fibrous histiocytoma. Cancer Res. 2000;60:6339–45.

    CAS  PubMed  Google Scholar 

  51. Pérot G, Chibon F, Montero A, Lagarde P, de Thé H, Terrier P, et al. Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics. Am J Pathol. 2010;177:2080–90.

    Article  Google Scholar 

  52. Gibault L, Pérot G, Chibon F, Bonnin S, Lagarde P, Terrier P, et al. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol. 2011;223:64–71.

    Article  CAS  Google Scholar 

  53. Cancer Genome Atlas Research Network. Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell. 2017;171:950–965.e28.

    Article  Google Scholar 

  54. Fletcher CDM, Bridge JA, Hogendoorm PCW. World Health Organization classification of tumours: pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press; 2012.

  55. Kirsch DG, Dinulescu DM, Miller JB, Grimm J, Santiago PM, Young NP, et al. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med. 2007;13:992–7.

    Article  CAS  Google Scholar 

  56. Dodd RD, Mito JK, Kirsch DG. Animal models of soft-tissue sarcoma. Dis Models Mech. 2010;3:557–66.

    Article  CAS  Google Scholar 

  57. Lazebnik Y. The shock of being united and symphiliosis. Another lesson from plants? Cell Cycle. 2014;13:2323–9.

    Article  CAS  Google Scholar 

  58. Ogle BM, Cascalho M, Platt JL. Biological implications of cell fusion. Nat Rev Mol Cell Biol. 2005;6:567–75.

    Article  CAS  Google Scholar 

  59. Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015;348:880–6.

    Article  CAS  Google Scholar 

  60. Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ, et al. Somatic mutant clones colonize the human esophagus with age. Science. 2018;362:911–7.

    Article  CAS  Google Scholar 

  61. Johnson RT, Rao PN. Mammalian cell fusion: induction of premature chromosome condensation in interphase nuclei. Nature. 1970;226:717–22.

    Article  CAS  Google Scholar 

  62. Rao PN, Johnson RT. Mammalian cell fusion: studies on the regulation of DNA synthesis and mitosis. Nature. 1970;225:159–64.

    Article  CAS  Google Scholar 

  63. Vignery A. Macrophage fusion. J Exp Med. 2005;202:337–40.

    Article  CAS  Google Scholar 

  64. Chen EH, Olson EN. Unveiling the mechanisms of cell-cell fusion. Science. 2005;308:369–73.

    Article  CAS  Google Scholar 

  65. Dittmar T, Zänker KS. Tissue regeneration in the chronically inflamed tumor environment: implications for cell fusion driven tumor progression and therapy resistant tumor hybrid cells. Int J Mol Sci. 2015;16:30362–81.

    Article  CAS  Google Scholar 

  66. Lu X, Kang Y. Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants. Proc Natl Acad Sci USA. 2009;106:9385–90.

    Article  CAS  Google Scholar 

  67. Ding J, Jin W, Chen C, Shao Z, Wu J. Tumor associated macrophage x cancer cell hybrids may acquire cancer stem cell properties in breast cancer. PLoS ONE. 2012;7:e41942.

    Article  CAS  Google Scholar 

  68. Giroux V, Rustgi AK. Metaplasia: tissue injury adaptation and a precursor to the dysplasia-cancer sequence. Nat Rev Cancer. 2017;17:594–604.

    Article  CAS  Google Scholar 

  69. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.

    Article  CAS  Google Scholar 

  70. Van Mater D, Xu E, Reddy A, Añó L, Sachdeva M, Huang W, et al. Injury promotes sarcoma development in a genetically and temporally restricted manner. JCI Insight. 2018;3:123687.

  71. Walsh S, Nygren J, Pontén A, Jovinge S. Myogenic reprogramming of bone marrow derived cells in a W41Dmdmdx deficient mouse model. PLoS ONE. 2011;6:e27500.

    Article  CAS  Google Scholar 

  72. Kovacs G. Premature chromosome condensation: evidence for in vivo cell fusion in human malignant tumours. Int J Cancer. 1985;36:637–41.

    Article  CAS  Google Scholar 

  73. Kovacs G, Georgii A. Spontaneous cell fusion in human malignancies: possible mechanism leading to heterogeneity. Lancet. 1985;1:350.

    Article  CAS  Google Scholar 

  74. Pérot G, Derré J, Coindre J-M, Tirode F, Lucchesi C, Mariani O, et al. Strong smooth muscle differentiation is dependent on myocardin geneamplification in most human retroperitoneal leiomyosarcomas. Cancer Res. 2009;69:2269–78.

    Article  Google Scholar 

  75. Commo F, Guinney J, Ferté C, Bot B, Lefebvre C, Soria J-C, et al. rCGH: a comprehensive array-based genomic profile platform for precision medicine. Bioinformatics. 2016;32:1402–4.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Fondation ARC pour la Recherche Contre le Cancer (to T.L.) and the Fondation Recherche Médicale (to L.L. and L.D.). We acknowledge personnel of CREFRE US006 for technical assistance.

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Author notes

  1. These authors contributed equally: Lucile Delespaul, Candice Merle

  2. These authors jointly supervised this work: Lydia Lartigue, Frédéric Chibon

Authors and Affiliations

  1. INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31037, Toulouse, France

    Lucile Delespaul, Candice Merle, Tom Lesluyes, Sophie Le Guellec, Gaëlle Pérot & Frédéric Chibon

  2. INSERM U1218, 229 cours de l’Argonne, 33076, Bordeaux, France

    Lucile Delespaul, Tom Lesluyes, Pauline Lagarde, Jessica Baud & Lydia Lartigue

  3. University of Bordeaux, 146 rue Léo Saignat, 33000, Bordeaux, France

    Lucile Delespaul, Tom Lesluyes, Jean-Michel Coindre & Lydia Lartigue

  4. University of Toulouse 3, Paul Sabatier, 118 route de Narbonne, 31062, Toulouse, Cedex 9, France

    Candice Merle

  5. Institut Claudius Régaud, IUCT-Oncopole, Toulouse, France

    Candice Merle & Tom Lesluyes

  6. Department of Biopathology, Bergonié Institute, 229 cours de l’Argonne, 33076, Bordeaux, France

    Pauline Lagarde, Jessica Baud & Jean-Michel Coindre

  7. Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, Toulouse, France

    Sophie Le Guellec, Gaëlle Pérot & Frédéric Chibon

  8. INSERM U1053, 146 rue Léo Saignat, 33000, Bordeaux, France

    Martina Carlotti

  9. Animal Facility A2, Bordeaux University, 146 rue Léo Saignat, 33000, Bordeaux, France

    Coralie Danet, Murielle Fèvre & Benoit Rousseau

  10. INSERM U1212 – CNRS UMR 5320, ARNA Laboratory, 33000, Bordeaux, France

    Stéphanie Durrieu & Martin Teichmann

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  1. Lucile Delespaul
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Delespaul, L., Merle, C., Lesluyes, T. et al. Fusion-mediated chromosomal instability promotes aneuploidy patterns that resemble human tumors. Oncogene 38, 6083–6094 (2019). https://doi.org/10.1038/s41388-019-0859-6

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