# Differential role of different NAD+ kinase Isoforms in melanoma metastasis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $387,731

## Abstract

PROJECT SUMMARY
Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically
target metastatic disease. Many of the current in vitro models of metastasis focus on the molecular mechanisms
of migration, invasion and/or surviving anoikis, but cannot recapitulate the complexity of the environment in which
metastasis occurs in vivo. Conversely, in mouse models of metastasis, it has been difficult to examine the
molecular mechanisms that enable cells to proceed through each distinct step of metastasis due to limited
material that can be isolated and infrequency of metastatic events in these models. For these reasons little is
known about the challenges facing metastasizing cells in vivo, and how they are overcome. We have previously
established a clinically relevant model of melanoma metastasis, using patient-derived xenografts (PDX) in
immunocompromised mice, that recapitulates the outcome of the disease of the patient in mice, to dissect the
metastatic cascade into distinct steps. Using this model, we have shown that metastasizing melanoma cells
undergo reversible metabolic adaptations to withstand oxidative stress in part through an increased dependence
on NADPH-generating enzymes in the one-carbon pathway. Our preliminary data also show an increase in
NADP+ levels in metastatic nodules compared to subcutaneous tumors, suggesting an increase in de novo
NADP+ synthesis. NADP+ is generated from NAD+ by NAD+ kinase (NADK). We observe higher levels of NADK
in metastatic nodules compared to subcutaneous tumors, where metastatic nodules express the isoform of
NADK with the highest activity, while subcutaneous tumors do not. We will test the hypothesis that metastasizing
melanoma cells upregulate a specific isoform of NADK to increase NADP+ production, increase oxidative stress
resistance and survival at different steps of the metastatic cascade.
Using both melanoma cell lines and PDX tumor cells, Aim 1 will determine the role of different NADK isoforms
in oxidative stress resistance, Aim 2 will define the mechanism of transcriptional regulation of NADK isoforms,
and Aim 3 will establish the role of different NADK isoforms as metastatic drivers in vivo. In addition, Aim 3 will
test how perturbation of oxidative stress in different organelles impacts metastasis. Together this work will
significantly contribute to our understanding of a novel mechanism of metabolic plasticity through upregulation
of a specific NADK isoform and identify organelle-specific metabolic pathways as novel therapeutically targetable
vulnerabilities in melanoma metastasis.

## Key facts

- **NIH application ID:** 10436014
- **Project number:** 1R01CA270885-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Elena Piskounova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,731
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436014

## Citation

> US National Institutes of Health, RePORTER application 10436014, Differential role of different NAD+ kinase Isoforms in melanoma metastasis (1R01CA270885-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436014. Licensed CC0.

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