Abstract IA11: Translating the cancer genome one codon at a time and its therapeutic implications

Abstract

Abstract Our research is centered on understanding translational control of gene expression in both normal health and disease in a cell- and tissue-specific manner, with a particular focus on cancer biology. Our research combines mouse genetics with genome-wide translational profiling, in-depth molecular biology, and pharmacology to systematically define the points of regulation, in cis and trans, by which the genome is selectively decoded into proteins. We have uncovered that a common denominator of multiple oncogenic pathways is their ability to directly control the core translation machinery of a cell, resulting in the rapid rewiring of mRNA translation programs that promote distinct hallmarks of cancer development such as cell growth, metabolism, and increased motility. For example, our most recent findings delineate the in vivo requirements for a distinct threshold of the major cap-binding protein, eIF4E, a key translation factor downstream of mTOR signaling, in normal organismal development compared to that required for translating the cancer genome. We show that cancer cells require increased eIF4E activity for their survival as distinct subsets of mRNAs that regulate the cancer cell oxidative response are marked by the presence of a novel eIF4E-dependent cis-acting translational control motif present in their 5'UTRs. I will also discuss the generation of the first comprehensive systems-level analysis of the “cancer translatome” during each phase of cancer development in vivo that highlights a dichotomy in transcriptional vs. translational control of gene expression guiding key, select steps in cancer development and evolution. These studies have uncovered a previously unappreciated translation program guiding tumor cell evasion of immune checkpoints. The immediate impact of our research has been the design of a new generation of compounds to target the aberrant translation machinery in cancer cells, which are currently in clinical trials and may reflect a new frontier in cancer therapy. Citation Format: Davide Ruggero. Translating the cancer genome one codon at a time and its therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA11.