CRISPR screens identify tumor-promoting genes conferring melanoma cell plasticity and resistance

ABSTRACT: Most genetic alterations that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non-genetic mechanisms that drive these processes. Here, we performed in vivo gain-of-function CRISPR screens and identified SMAD3, BIRC3 and SLC9A5 as key actors of BRAFi-resistance. We show that their expression levels increase during acquisition of BRAFi-resistance, and remain high in persister cells and during relapse. The upregulation of the SMAD3 transcriptional activity (SMAD3-signature) promotes a mesenchymal-like phenotype and BRAFi-resistance by acting as an upstream transcriptional regulator of potent BRAFi-resistance genes such as EGFR and AXL. This SMAD3-signature predicts

SUBMITTER: Arthur Gautron 

PROVIDER: S-SCDT-EMM-2020-13466 | biostudies-other |

REPOSITORIES: biostudies-other