# The Metabolic Regulation of Melanoma Metastasis

> **NIH NIH U01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $840,635

## Abstract

ABSTRACT
Most cancer deaths are caused by distant metastasis. Yet the mechanisms that regulate distant metastasis are
poorly understood. Metastasis is a very inefficient process in which few disseminated cancer cells survive, and
even fewer proliferate, but it is not known why. We developed a patient-derived xenograft (PDX) assay in
which melanomas engraft very efficiently and spontaneously metastasize. Using this assay, we discovered
intrinsic differences in metastatic potential among melanomas from different patients. Some stage III
melanomas are “efficient metastasizers” that spontaneously form distant metastases in patients and in NSG
mice while others are “inefficient metastasizers” that do not form distant macrometastases in patients or in
NSG mice under the same experimental conditions. Using this assay, we discovered that melanoma cells
experience a spike in reactive oxygen species (ROS) during metastasis and that distant metastasis is limited
by oxidative stress. Successfully metastasizing cells undergo reversible metabolic changes during metastasis
that increase their capacity to withstand oxidative stress, including increased folate pathway dependence.
However, the mechanisms that confer differences in metastatic potential upon melanomas from different
patients have not yet been identified. We hypothesize that efficiently and inefficiently metastasizing melanomas
have intrinsic metabolic differences that reduce oxidative stress in efficient metastasizers. One impediment to
testing this hypothesis is that melanomas from patients grow poorly at clonal density in known culture
conditions, preventing certain approaches for studying cancer metabolism and the use of CRISPR gene editing
(because single cell-derived clones could not be screened or expanded). We spent years developing a culture
medium in which single melanoma cells from patients form tumor organoids (PDOs). This capability raises the
general question of whether metabolism and oxidative stress resistance are regulated similarly in PDXs and in
PDOs. To address this question, we will compare, side-by-side, the biological properties and metabolic
regulation of efficient and inefficient metastasizers in PDXs and PDOs. We will test if efficiently metastasizing
melanomas have lower ROS levels or markers of oxidative stress, or increased use of the folate or pentose
phosphate pathways, as compared to inefficient metastasizers, and whether this promotes metastasis in PDXs
or migration/invasion in PDOs. We will also test if MCT1, a lactate transporter, promotes metastasis and
whether efficient metastasizers reduce oxidative stress partly through lactate exchange. Finally, we will test if
there are intrinsic differences in mitochondrial function between efficient and inefficient metastasizers that
reduce ROS generation. By comparing the biological properties and metabolic regulation of each melanoma in
PDX and PDO assays, we will assess the strengths and weaknesses of PDX and PDO assays f...

## Key facts

- **NIH application ID:** 10469624
- **Project number:** 5U01CA228608-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** SEAN J MORRISON
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $840,635
- **Award type:** 5
- **Project period:** 2019-09-05 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469624

## Citation

> US National Institutes of Health, RePORTER application 10469624, The Metabolic Regulation of Melanoma Metastasis (5U01CA228608-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469624. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*