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Genome remodeling upon mesenchymal tumor cell fusion contributes to tumor progression and metastatic spread

Oncogene volume 39, pages 4198–4211 (2020)Cite this article

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Abstract

Cell fusion in tumor progression mostly refers to the merging of a cancer cell with a cell that has migration and immune escape capabilities such as macrophages. Here we show that spontaneous hybrids made from the fusion of transformed mesenchymal cells with partners from the same lineage undergo nonrecurrent large-scale genomic rearrangements, leading to the creation of highly aneuploid cells with novel phenotypic traits, including metastatic spreading capabilities. Moreover, in contrast to their parents, hybrids were the only cells able to recapitulate in vivo all features of human pleomorphic sarcomas, a rare and genetically complex mesenchymal tumor. Hybrid tumors not only displayed specific mesenchymal markers, but also combined a complex genetic profile with a highly metastatic behavior, like their human counterparts. Finally, we provide evidence that patient-derived pleomorphic sarcoma cells are inclined to spontaneous cell fusion. The resulting hybrids also gain in aggressiveness, exhibiting superior growth capacity in mouse models. Altogether, these results indicate that cell fusion has the potential to promote cancer progression by increasing growth and/or metastatic capacities, regardless of the nature of the companion cell. Moreover, such events likely occur upon sarcoma development, paving the way for better understanding of the biology, and aggressiveness of these tumors.

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Fig. 1: Hybrid fluorescence expression and DNA content.
Fig. 2: Hybrid’s genome characterization.
Fig. 3: Hybrids display higher invasive properties in vivo.
Fig. 4: Hybrids do not gain proliferative advantages but exhibit higher invasive capacities in vitro.
Fig. 5: Genetic consequences of sarcoma cell fusion.
Fig. 6: Phernotypic changes in sarcoma hybrids.
Fig. 7: IB105/106 hybrids generate tumors in NSG mice, while IB105-DsRed or IB106-GFP parental cells do not.

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Acknowledgements

This work was supported by the “Fondation ARC pour la recherche contre le cancer”, “the Fondation pour la recherche médicale” (FRM), and the associations “Phil’Anthrope” and “Pour Corentin”.

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Authors and Affiliations

  1. INSERM U1218, 229 cours de l’Argonne, F-33076, Bordeaux, France

    Lydia Lartigue, Pauline Lagarde, Jean-Michel Coindre & Frédéric Chibon

  2. Bordeaux University, 146 rue Léo Saignat, F-33000, Bordeaux, France

    Lydia Lartigue, Pauline Lagarde & Jean-Michel Coindre

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

    Candice Merle, Lucile Delespaul, Tom Lesluyes, Sophie Le Guellec, Gaelle Pérot, Laura Leroy & Frédéric Chibon

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

    Candice Merle

  5. Department of Biopathology, Bergonie Institute, 229 cours de l’Argonne, F-33076, Bordeaux, France

    Pauline Lagarde, Jean-Michel Coindre & Frédéric Chibon

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

    Sophie Le Guellec, Gaelle Pérot, Laura Leroy & Frédéric Chibon

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  1. Lydia Lartigue
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Contributions

LL, CM, and LD performed most of the experiments; PL generated hybrid and sarcoma cell lines; GP and LL performed some CGHs and immunostaining; TL performed the bioinformatics analyses; SLG and JMC did the histology analyses; LL and FC integrated and analyzed the data; LL and FC wrote the article with the help of CM; FC designed the study, supervised all the work, and obtained financial support.

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Correspondence to Frédéric Chibon.

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Lartigue, L., Merle, C., Lagarde, P. et al. Genome remodeling upon mesenchymal tumor cell fusion contributes to tumor progression and metastatic spread. Oncogene 39, 4198–4211 (2020). https://doi.org/10.1038/s41388-020-1276-6

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