Grant: Project Grant

Recent breakthroughs in gene editing technologies have transformed mammalian cell genetics and disease research. In particular, genome-scale screens employing CRISPR-Cas nucleases have already started delivering unprecedented insight into genotype-to-phenotype relationships. For example, such screens have defined genes required for human cell line proliferation that share functional, evolutionary, and physiological properties with essential genes in other organisms. These studies have ushered in a new era of functional genomics by enabling the systematic perturbation and characterization of genes in human cells that underlie biological processes and phenotypes. During the last funding stage, our team has made pioneering contributions to the development of world class genome-wide CRISPR resources for screening all human and mouse protein coding genes. The complexity of genome-wide CRISPR-Cas screening data led to the development of databases, computational models and machine learning to quantify gene perturbation effects in cancer cell models and under different environmental conditions. In one recent study we performed genetic screens on biological processes that impinged on lipid metabolism and were able to identify an uncharacterized gene that is required for regulation of lipid uptake, which we named LUR1. This study also highlighted how cellular metabolic reprogramming can be dissected by studying genetic interactions. Importantly, deregulated cellular energetics is a hallmark of cancer and we are interested in understanding how cancer cells adapt to changing environmental and metabolic conditions in order to reprogram their metabolism for robust tumor growth. We propose to take a systematic approach to identify and validate targets that can be modulated by drugs and impact cancer outcomes.