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

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $404,626

## 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.

## Key facts

- **NIH application ID:** 10835924
- **Project number:** 5R01CA270241-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Clara Theresa Vincent
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $404,626
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835924

## Citation

> US National Institutes of Health, RePORTER application 10835924, Translation regulation of the mesenchymal transition by the rRNA and mRNA m6A axis (5R01CA270241-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10835924. Licensed CC0.

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