# Investigating the role of nucleotide metabolism and AMPK signaling in melanoma metastasis

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $47,269

## Abstract

PROJECT SUMMARY/ABSTRACT
Metastasis, the spread of cancer cells from primary tumor to distant organs, accounts for 90% of solid tumor
related mortality. The metabolic changes underlying this multistep cascade remain poorly understood. Recent
work from our laboratory demonstrated that oxidative stress limits melanoma metastasis. Metastasizing cells
utilize the one-carbon cycle to regenerate NADPH and combat oxidative stress. This increase in the NADPH-
regenerating arm of one-carbon metabolism may limit the availability of substrates for other processes within the
one-carbon cycle, including intermediates for purine biosynthesis. Consistent with this hypothesis, our
preliminary data has shown that metastatic nodules have significantly higher levels of AICAR compared to
subcutaneous tumors, suggesting a block in the de novo purine biosynthesis pathway. AICAR, an adenosine
monophosphate analogue, is an allosteric activator of AMPK. We observe increased activation of AMPK in
metastatic nodules compared to subcutaneous tumors. AMPK regulates the metabolic homeostasis by switching
metabolism from anabolic to catabolic state thereby increasing cell survival in nutrient scarce conditions. I
hypothesize that metastasizing cells preferentially rely on the salvage pathway and upregulate AMPK signaling,
thereby switching to a catabolic metabolism to survive the hostile conditions of visceral organs. My proposal
uses a clinically relevant model of melanoma metastasis in which patient-derived xenografts are transplanted
into immunocompromised mice. Using this system, I will dissect the metabolic cascade and identify metabolic
alterations that allow metastasizing melanoma cells to survive. In aim 1 of this proposal, I will ask whether
metastasizing cells preferentially utilize the nucleotide salvage pathway during metastasis. In aim 2 of this
proposal, I will investigate the role of AMPK signaling in promoting survival of metastasizing cells in circulation
and upon colonization of distant organs. Successful completion of these aims will uncover the metabolic
adaptations which allow metastasizing cells to survive and identify actionable targets to combat metastatic
spread.

## Key facts

- **NIH application ID:** 9843436
- **Project number:** 5F30CA236302-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Kristina Navrazhina
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,269
- **Award type:** 5
- **Project period:** 2018-12-17 → 2022-12-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843436

## Citation

> US National Institutes of Health, RePORTER application 9843436, Investigating the role of nucleotide metabolism and AMPK signaling in melanoma metastasis (5F30CA236302-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843436. Licensed CC0.

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