ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue EMBO Journal Année : 2019

ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas

Résumé

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.
Fichier principal
Vignette du fichier
ROCK2 inhibition triggers the collective invasion of colorectal adenocarcinomas.pdf (4.44 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-02361455 , version 1 (13-11-2019)

Identifiants

Citer

Fotine Libanje, Joël Raingeaud, Rui Luan, Zoe Thomas, Olivier Zajac, et al.. ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas. EMBO Journal, 2019, 38 (14), ⟨10.15252/embj.201899299⟩. ⟨hal-02361455⟩
39 Consultations
125 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More