Translation regulation of the mesenchymal transition by the rRNA and mRNA m6A axis

New York University School Of Medicine, New York NY

Investigators

Abstract

PROJECT SUMMARY Currently there are no effective treatments that can cure metastatic breast cancer. The epithelial-to- mesenchymal transition (EMT) is a critical cancer cell plasticity and dedifferentiation program by which epithelial cells acquire pro-migratory and invasive mesenchymal properties. To initiate the EMT program, cancer cells need to receive pro-EMT signals, such as TGF from either neighboring tumor cells or from the microenvironment (surrounding stroma). Our research group made the unexpected finding that during TGFβ mediated EMT, Pol I rDNA transcription is: (1) driven by Snail, a transcription factor known to play a central role in orchestrating the mesenchymal Pol II dependent gene expression program required for cellular invasiveness and metastatic spread; (2) a concurrent loss of Myc occurs at rDNA genes; and (3) Snail forms a complex with METTL5 to enable that the newly made rRNA are m6A modified by METTL5 before the rRNA is incorporated into the mature ribosome; (4) Snail also forms a complex with METTL3 and may therefore direct m6A modifications of selective mRNAs; (5) the m6A marked mRNAs enables recruitment of the non-canonical DAP5/eIF3d/METTL3 translation complex to drive selective m6A marked mRNA translation in the mesenchymal state; and (6) METTL5 is required for execution of the EMT program, as silencing of METTL5 prevents cells from undergoing EMT. The focus of this grant application is to gain a deeper molecular understanding of Pol I rDNA transcription, METTL5 m6A modified rRNA and ribosomes and why selective DAP5/eIF3d mediated translational control is essential for orchestrating breast cancer cell plasticity in EMT, its role in breast cancer metastatic progression, and how Snail orchestrates and coordinates the m6A rRNA/mRNA axis. This knowledge will ultimately inform how targeting Pol I machinery, specialized ribosomes and translation control could represent a novel therapy specifically targeting the plastic, non-proliferating and chemo-resistant EMT cells fueling tumor reoccurrence and metastasis.