# Non-canonical WNT signaling in the invasion and metastasis of uveal melanoma

> **NIH NIH F30** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $51,036

## Abstract

PROJECT SUMMARY
 Uveal melanoma (UM) is the most common primary ocular malignancy. In approximately 50% of patients,
UM progresses into a metastatic disease, with the liver being the most common site of metastasis. Once this
occurs, prognosis is dismal, with a median survival of less than one year. There are very few effective
therapies for metastatic UM, in part due to the paucity of knowledge regarding the molecular mechanisms that
control the invasion and metastasis of UM cells. A WNT family ligand, WNT5A, has been implicated in the
invasion and metastasis of several different cancers, but its role in UM is unknown. One way by which WNT5A
promotes these processes is by binding receptor tyrosine kinase-like orphan receptor 2 (ROR2) and
stimulating its internalization. This is required to activate downstream targets that control invasion, such as
protein kinase C (PKC). The small GTPase ARF6 is required for the invasion of several types of cancer, is
activated by WNT5A in cutaneous melanoma, and is known to regulate the trafficking of receptors at the cell
surface. Preliminary data suggest that WNT5A expression is elevated and activates ARF6 in some UM cells.
The first aim of this research is to determine whether a WNT5A-ROR2-ARF6 axis controls invasion and
metastasis of UM. Key methods include Matrigel invasion assays, a murine xenograft model of metastatic UM,
and pharmacologic targeting of ARF6 with novel small molecule inhibitors. The second aim is to dissect the
mechanism by which ARF6 mediates WNT5A-ROR2 signaling. We will use cellular fractionation assays,
immunofluorescence staining and western blotting to study the role of ARF6 in the trafficking and signaling of
ROR2. This work has also identified a potential complex containing ROR2 and β-catenin in the nucleus of UM
cells. The other major aim of the proposal is to elucidate the function of nuclear ROR2 and determine whether
it alters β-catenin transcriptional activity to promote invasion and metastasis of UM. This will be accomplished
using ROR2 knockout UM cell lines and ectopic expression of ROR2 nuclear localization mutants. mRNA-Seq
data from these cells will be analyzed to reveal global expression changes and specific alterations in the β-
catenin transcriptional signature. Overall, we expect the proposed project to reveal a new pathway that could
be targeted to combat metastasis of uveal melanoma. This research also has the potential to uncover a critical
function of nuclear ROR2 that is likely conserved in other cancers and developmental processes.

## Key facts

- **NIH application ID:** 10129301
- **Project number:** 5F30CA217184-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** JACKSON ROYAL RICHARDS
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129301

## Citation

> US National Institutes of Health, RePORTER application 10129301, Non-canonical WNT signaling in the invasion and metastasis of uveal melanoma (5F30CA217184-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10129301. Licensed CC0.

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