Sequencing_of_SW837_cells_following_CDS2_gRNA_transduction_and_selection__Transcriptome_sequencing_of_mouse_tumors
Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options and poor survival outcomes. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in a collection of extensively profiled human uveal melanoma cell line models using genome-wide single gene/gRNA and combinatorial paired gene/paired gRNA CRISPR libraries. Within our identified uveal melanoma-specific essential genes and synthetic lethal gene pairs, we identified and validated CDS2 as a novel genetic dependency in the context of low CDS1 expression. We further demonstrate that CDS1/CDS2 is a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis, critical for the regulation of the MAPK and PI3K-Akt signalling pathways. We extend this analysis using pan-cancer data confirming increased CDS2 essentiality in diverse tumour types with low CDS1 expression. In this sequencing project we explore the genetic effects of CDS2 loss.