Reuven Agami Group
Controlling cancer by RNA
Our main research objective is to understand the genomic, epigenomic, and metabolic changes leading to cancer in humans – with the purpose of identifying points of vulnerabilities that can be exploited for cancer therapy. We use various state-of-the-art genomic tools to interrogate tumor behavior, gene alterations, and events that are fundamental to cancer development and survival. The knowledge obtained on these cancer dependencies allows us to design novel therapeutic approaches.
Research line 1: mRNA translation
In recent years, we established in the lab ribosome profiling technology to map with nucleotide precision ribosome position on mRNAs. This technology allows studying events regulated at the mRNA translation level. We have exploited this technology in the study of the tumor suppressor p53, translation in the mitochondria, and in response to oncogenic Myc activation. Most significantly, we have developed Diricore, a platform for the discovery of novel amino acid vulnerabilities in cancer.
Research line 2: Enhancers
Enhancers are non-coding genomic regions that activate gene expression of distantly located target genes. Interestingly, genes encoding enhancer-binding proteins were linked to cancer development, and novel cancer therapies block enhancer function. While the human genome contains almost a million different enhancers - only few are potentially involved in cancer. We studied the tumor suppressor p53, and showed that it binds enhancers, which produce enhancer RNAs (eRNAs) that are required for enhancer activity. Recently, we developed a CRISPR-Cas9 approach to identify oncogenic and tumor suppressive enhancers.
Research line 3: Regulation of alternative polyadenylation (APA)
APA emerged as an important layer of gene regulation as the majority of mammalian genes were already demonstrated to contain multiple polyadenylation (poly(A) sites in their 3' UnTranslated Regions (3’UTRs). Significant change in APA is observed when cells were stimulated to proliferate, differentiate, and during cancer progression. We uncovered the role of in APA and link it with a human genetic disorder and to cancer.