ROCK2 inhibition triggers the collective invasion of colorectal adenocarcinomas

Fotine Libanje, Joel Raingeaud, Rui Luan, ZoéAp Thomas, Olivier Zajac, Joel Veiga, Laetitia Marisa, Julien Adam, Valerie Boige, David Malka, Diane Goéré, Alan Hall, Jean Yves Soazec, Friedrich Prall, Maximiliano Gelli, Peggy Dartigues, Fanny Jaulin

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

The metastatic progression of cancer is a multi-step process initiated by the local invasion of the peritumoral stroma. To identify the mechanisms underlying colorectal carcinoma (CRC) invasion, we collected live human primary cancer specimens at the time of surgery and monitored them ex vivo. This revealed that conventional adenocarcinomas undergo collective invasion while retaining their epithelial glandular architecture with an inward apical pole delineating a luminal cavity. To identify the underlying mechanisms, we used microscopy-based assays on 3D organotypic cultures of Caco-2 cysts as a model system. We performed two siRNA screens targeting Rho-GTPases effectors and guanine nucleotide exchange factors. These screens revealed that ROCK2 inhibition triggers the initial leader/follower polarization of the CRC cell cohorts and induces collective invasion. We further identified FARP2 as the Rac1 GEF necessary for CRC collective invasion. However, FARP2 activation is not sufficient to trigger leader cell formation and the concomitant inhibition of Myosin-II is required to induce invasion downstream of ROCK2 inhibition. Our results contrast with ROCK pro-invasive function in other cancers, stressing that the molecular mechanism of metastatic spread likely depends on tumour types and invasion mode.

Original languageEnglish
Article numbere99299
JournalEMBO Journal
Volume38
Issue number14
DOIs
StatePublished - 15 Jul 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Keywords

  • GTPases
  • collective migration
  • colorectal carcinoma
  • invasion
  • leader cells

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