Seminario Mining existing and newly designed CRISPR screens to map genomic, transcriptomic and phenotypic contexts of cancer dependencies

Large-scale CRISPR screening efforts have enabled the systematic identification of genetic dependencies across diverse cancer models. However, most vulnerabilities are not universal, but arise within specific molecular or phenotypic contexts. Understanding these contexts is therefore essential to translate dependency maps into actionable therapeutic opportunities. I will present a set of complementary strategies to map the genomic, transcriptomic and phenotypic contexts that define cancer dependencies by mining both existing and newly designed CRISPR perturbation screens. First, I will describe a computational framework to identify mutation-specific vulnerabilities by leveraging large-scale CRISPR screening datasets, enabling high-resolution functional interpretation of variants of uncertain significance. Second, I will introduce DepSHOCK, an approach that combines computational modelling with targeted perturbation experiments to uncover transcriptional signatures predictive of cancer dependencies. Finally, I will discuss experimental strategies to identify vulnerabilities that emerge in drug-resistant states. Together, these approaches aim to move from cataloguing dependencies to systematically defining the contexts that make them actionable.