Abstract

Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed throughout the process of dissemination. TSIPs form and propagate through the collective apical budding of hypermethylated CRCs downstream of canonical and non-canonical transforming growth factor-β signalling. TSIPs maintain their apical-out topology and use actomyosin contractility to collectively invade three-dimensional extracellular matrices. TSIPs invade paired patient peritoneum explants, initiate metastases in mice xenograft models and correlate with adverse patient prognosis. Thus, despite their epithelial architecture and inverted topology TSIPs seem to drive the metastatic spread of hypermethylated CRCs.

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Acknowledgements

We thank all the patients who participated in this study and the medical staff for their assistance with the acquisition of primary human specimens. We also thank the members of the Jaulin Lab and the Digestive Cancer Unit for discussion, B. Baum for mentoring and support, and S. Deborde, B. Goud and G. Kreitzer for critical reading of the manuscript. We thank D. Vignjevic, S Guilmeau, the Plateforme Anticorps Recombinant (Curie Institute), DSHB (University of Iowa) and J. Zuber for reagents and the technical services provided by PFIC core facility, module HCP (F. Drusch and V. Marty), O. Bawa, V. Roufiac, S. Piterboth and I. Villa. This work was supported by the CNRS and INSERM (the ATIP-AVENIR program), the Gustave Roussy Foundation (Roulons pour le colon, Natixis), Canceropole (Emergence) Taxe d’apprentissage Gustave Roussy (2016 to C.C.J.).

Author information

Author notes

    • Olivier Zajac

    Present address: Department of Translational Research, Institut Curie, Paris, France

Affiliations

  1. U-981, Gustave Roussy, Villejuif, France

    • Olivier Zajac
    • , Joel Raingeaud
    • , Fotine Libanje
    • , Celine Lefebvre
    • , Dora Sabino
    • , Pétronille Roy
    • , Clara Benatar
    • , Charlotte Canet-Jourdan
    • , Paula Azorin
    • , Damien Nowak
    • , Ludovic Bigot
    •  & Fanny Jaulin
  2. Université Paris Saclay, Villejuif, France

    • Isabelle Martins
    •  & Jean-Luc Perfettini
  3. U-1030, Gustave Roussy, Villejuif, France

    • Isabelle Martins
    •  & Jean-Luc Perfettini
  4. Plateforme d’Evaluation Préclinique, AMMICA UMS 3655/ US 23, Gustave Roussy, Villejuif, France

    • Mélanie Polrot
    •  & Patrick Gonin
  5. UMR-1170, Gustave Roussy, Villejuif, France

    • Salima Benbarche
    •  & Camille Lobry
  6. UMR-9196, Gustave Roussy, Villejuif, France

    • Sylvie Souquere
    •  & Gerard Pierron
  7. Digestive Cancer Unit, Gustave Roussy, Villejuif, France

    • Michel Ducreux
    • , David Malka
    • , Dominique Elias
    •  & Diane Goéré
  8. Pathology Department, Gustave Roussy, Villejuif, France

    • Jean-Yves Scoazec
    •  & Peggy Dartigues
  9. UMR-965, Lariboisière Hospital, Paris, France

    • Clarisse Eveno
    •  & Marc Pocard

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Contributions

O.Z., J.R., F.L., D.S., S.S., G.P., I.M., P.R., C.B., P.A. and J.-L.P. designed the research, performed the experiments and analysed the data. L.B., M. Polrot and P.G. carried out the mice experiments. C.L. analysed the microarray and RNA-sequencing data. D.E., D.G., C.E., M. Pocard, M.D. and D.M. provided clinical samples. P.D. and J.-Y.S. performed the histological analyses. F.J. conceived the project, designed the research and wrote the manuscript. All authors provided intellectual input.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Fanny Jaulin.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–8 and legends for Supplementary Tables and Supplementary Videos.

  2. Life Sciences Reporting Summary

  3. Supplementary Table 1

    Patient data

  4. Supplementary Table 2

    Signalling pathways

  5. Supplementary Table 3

    Pathway mutations

  6. Supplementary Table 4

    Antibody information

  7. Supplementary Video 1

  8. Supplementary Video 2