# Molecular Mechanisms underlying tRNA-fragment regulation of cancer

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $454,192

## Abstract

In order for cancers to progress, metastasize, and become treatment refractory, gene
expression programs must be modulated. Transcriptional programs generate transcripts within
the cells, while post-transcriptional programs regulate the half-lives, localization, and
translational efficiency of cellular transcripts. Such post-transcriptional deregulation has been
implicated as a major means by which ‘aggressive’ gene expression progression are
established. We recently showed that RNA-fragments (tRF’s) generated from the processing of
specific tRNA molecules suppress breast cancer metastasis through their binding and
repression of an oncogenic RNA-binding protein (Goodarzi et al., Cell, 2015). A search for a tRF
that could promote cancer progression has led to our identification of a specific tRNA-fragment
(tRF) that is increased in highly metastatic breast cancer cells, promotes metastasis, and
suppresses expression of transcripts containing its recognition motif. This mode of regulation
contrasts RNAi-based mechanisms, since the modulated transcripts contain sense (rather than
complementary) sequences relative to the tRF. We hypothesize that this tRF drives metastatic
progression by binding and inhibiting an RNA-binding protein (RBP) that otherwise promotes the
stability of pro-metastatic transcripts. We aim to investigate the role of this tRF in metastasis
formation and progression; to identify the trans-factor (RBP) that this tRF regulates and the
downstream regulon impacted; to uncover the upstream mechanism of tRF generation; to
investigate its diagnostic potential as a predictive biomarker; and to provide proof-of-concept
support for tRF therapeutic inhibition through oligonucleotide anti-sense administration. We will
utilize cutting-edge, complementary, and mutli-disciplinary methods to achieve these goals.
Successful completion of this study will generate new basic insights into post-transcriptional
regulation by a tRNA-derived fragment, reveal how specificity is achieved in tRNA-fragment
generation, achieve proof-of-concept for oligonucleotide-based therapeutic inhibition of a tRF in
cancer, identify a potentially druggable tRF-producing ribonuclease, and establish diagnostic
and prognostic potential for a tRF. As such, this work has significant potential for impacting
human health. Our lab has made major mechanistic inroads into the non-canonical roles of
tRNAs in gene-expression control in cancer (Goodarzi, Hoang et al., Cell, 2016; Goodarzi et al.,
Cell, 2015). Moreover, our interdisciplinary approach that integrates molecular, biochemical,
genetic, computational, animal modeling, and clinical association methods to investigate basic
mechanistic questions of relevance to human cancer position us well for success in these efforts.

## Key facts

- **NIH application ID:** 9869697
- **Project number:** 5R01CA215491-04
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Sohail F. Tavazoie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,192
- **Award type:** 5
- **Project period:** 2017-03-17 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869697

## Citation

> US National Institutes of Health, RePORTER application 9869697, Molecular Mechanisms underlying tRNA-fragment regulation of cancer (5R01CA215491-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869697. Licensed CC0.

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