NIH Reporter #1ZIABC012100-04

Unravelling Metabolic Plasticity Through Genetic Interaction Mapping.

This award funds research using CRISPR screening to map genetic interactions in cancer cell metabolism, aiming to identify key regulators and potential therapeutic targets for cancer treatment.

Description

We use our CHyMErA CRISPR screening platform for the mapping of genetic interactions through acute, combinatorial gene perturbation. We designed a genetic interaction library targeting genes involved in central metabolism and its regulation, enabling the experimental interrogation for genetic interactions between thousands of gene pairs. We applied this library in human cells cultured in both nutrient-rich and physiologically relevant media. Our pairwise gene knockout screens uncovered dozens of positive and negative genetic interactions between core metabolic enzymes and nutrient transporters, some of which are conditionally dependent on the composition of the growth media. In addition, we also captured known functional redundancies between paralogous genes. Network analysis revealed multiple genetic interaction hubs that may present key regulators of metabolic plasticity. These and other genetic interactions are currently being investigated mechanistically to understand how cancer cells adapt to nutrient-limiting environmental conditions and to identify potential combinatorial targets or biomarkers for cancer treatment strategies.

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