09/03-2020 - Coralie Dorard : Rôle of raf1 in colorestal carcingenesis in 3D models
06 - Mars - 2020
LES LUNDIS DE SAINT-ANTOINE
Bâtiment Kourilsky - 13h–14h
Salle des Conférences (Rez de Chaussée),
184 rue du Faubourg Saint-Antoine, Paris
LUNDI 09 MARS 2020
Rôle of raf1 in colorestal carcingenesis in 3D models
Centre de Recherche Saint-Antoine
Equipe Alex Duval (firstname.lastname@example.org)
More than 30% of all human cancers are driven by mutations in RAS oncogenes. The MAPK pathway is a conserved signaling cascade implicated in many cellular processes connected with tumorigenesis. Studies in RAS-driven tumors in animal models have shown essential roles of the RAS effectors RAF, which can be dependent or independent of their ability to activate the MEK/ERK module. In particular, the RAF paralog RAF1 exerts unique essential functions in the control of apoptosis, cell migration, cell-cell adhesion and differentiation, and had been shown to be essential downstream of mutated RAS in squamous cell carcinoma and lung carcinoma development. At present, little is known about its specific functions in colorectal cancer (CRC), while activating KRAS mutations represent 40% of CRC. Since KRAS-driven CRC is resistant to most treatments, a full understanding of the biological mechanisms downstream of mutated KRAS is essential for the development of new targeted therapies.
We are performing a systematic comparison of the cell-autonomous phenotypes of KRAS-mutated (or not) MSI (MicroSatellite Instability) and CIN (Chromosomal INstability) CRC cell lines by using 3D spheroid models. We started to assess the biological processes impacted by RAF1 ablation (generated by CRISPR/Cas9 genome editing) or inducible silencing (by Tet-inducible shRNA) by monitoring spheroid formation and maintenance. Mechanistic studies are ongoing to characterize the specific roles of RAF1 in colorectal carcinogenesis. This screening of 3D spheroids correlated with further results we will obtained in human organoids will identify new RAF1-related vulnerabilities in CRC which could pave the road for the design of new targeted therapies.