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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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.).
The authors declare no competing financial interests.
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Zajac, O., Raingeaud, J., Libanje, F. et al. Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas. Nat Cell Biol 20, 296–306 (2018). https://doi.org/10.1038/s41556-017-0027-6
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