Abstract 4766: Translation from unconventional 5' start sites drives tumor initiation

How translational control impacts tumor-initiation and malignancy is just beginning to unfold. Here, we devise an epidermis-specific, in vivo ribosome profiling strategy to interrogate the translational landscape during the transition from normal homeostasis to malignancy. Inducing SOX2, broadly expressed in oncogenic RAS-associated cancers, we find that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. Seeking mechanism, we find that during tumor-initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing translational efficiency of oncogenic mRNAs. An in vivo RNAi screen of translational regulators revealed that dampening conventional EIF2 complexes has dire consequences for normal but not oncogenic growth. Conversely, we identify alternative initiation factors essential for cancer progression, where they mediate initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a hitherto unappreciated role of 5’UTR translation in cancer, and expose new targets for therapeutic intervention. Citation Format: Ataman Sendoel, Joshua G. Dunn, Edwin H. Rodriguez, Shruti Naik, Nicholas C. Gomez, Brian Hurwitz, John Levorse, Brian D. Dill, Daniel Schramek, Henrik Molina, Jonathan S. Weissman, Elaine Fuchs. Translation from unconventional 59 start sites drives tumor initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2017-4766