# Regulation of the Selenocysteine Stress Response in Cancer Metastasis

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $46,752

## Abstract

PROJECT SUMMARY
The adaptations that metastasizing cancer cells undergo are not well understood, contributing to a lack of
effective therapies, making metastasis the leading cause of cancer-related deaths. Genetic drivers of metastatic
progression have not been identified, thus it is imperative to study the disease at the transcriptional and
translational level where cells are able to make reversible adaptations that allow them to survive throughout the
metastatic cascade. Our long-term goal is to find novel and targetable vulnerabilities in cancer metastasis by
identifying these molecular and metabolic adaptations. Early work from our lab shows that metastasizing cells
undergo high levels of oxidative stress. Selenocysteine, the 21st amino acid, is incorporated into a family of
proteins that are involved in detoxifying reactive oxygen species and maintaining redox balance in the cell.
Translation of selenoproteins under cellular stress is regulated by a single 2’-O-ribose methylation on the wobble
uridine (Um34) of the selenocysteine tRNA (tRNASec), completed by an unknown methyltransferase. Using our
lab’s patient-derived tumor model of melanoma metastasis, I will test the hypothesis that Um34 methylation
is increased in metastasizing cells and that this modification increases cell survival under oxidative
stress by regulating a subset of stress response selenoproteins. To address this question, I will utilize an
established patient-derived melanoma model where metastasis is predictive of patient outcome in parallel with
melanoma cell lines in vitro. In Aim 1, I will determine the functional role of Um34 in metastasis and the oxidative
stress response. I will develop tools to measure Um34 levels and I will perturb the modification event by targeting
related enzymes, tRNASec and selenium availability. In Aim 2, I will identify the unknown Um34 methyltransferase
by testing a candidate protein and through targeted immunoprecipitation approaches. I will use mass
spectrometry to quantify Um34 levels and identify related protein complexes. I will then characterize the
selenocysteine stress response and through depletion of the identified methyltransferase, I will determine its
functional role in metastasis and the oxidative stress response. This work will be completed at Weill Cornell
Medicine where I will develop scientifically and professionally into an independent researcher. I will receive
expert guidance throughout my project from my committee of world-renowned scientists whose expertise span
the many fields covered in my proposal. Through this work I will master biochemical analytical techniques,
modeling a complicated disease in vivo and clearly communicating my ideas and results – all of which will
prepare me for a career as an independent investigator in academic science. Identifying novel targets in
metastatic disease is an urgent therapeutic need and I believe that this work will not only find one, but expand
the current understanding of h...

## Key facts

- **NIH application ID:** 10445241
- **Project number:** 5F31CA254235-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Leona Nease
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-07-14 → 2023-07-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445241

## Citation

> US National Institutes of Health, RePORTER application 10445241, Regulation of the Selenocysteine Stress Response in Cancer Metastasis (5F31CA254235-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445241. Licensed CC0.

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