# Defining Transcriptional Regulators of Melanoma Initiation using Zebrafish

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $360,751

## Abstract

Project Summary/Abstract
 Within a group of cancer-prone cells that share an oncogenic mutation, sometimes described as a
“cancerized field”, only select cells transition to a malignant state. Due to the rarity and transient nature of these
events, cancer initiation has been difficult to study and remains incompletely understood. Identifying cells at the
earliest stages of transformation and understanding the underlying mechanisms leading to their malignant
conversion would allow for earlier detection and treatment of cancer, which should lead to better patient
outcomes. Such is the case in the skin, where non-cancerous overgrowths of pigmented melanocytes, called
nevi or moles, harbor a potentially cancer-causing mutation, termed BRAFV600E, which is also found in over half
of melanoma cancers. Yet nevi rarely progress to invasive melanoma.
 To enable studies of melanoma initiation and the mechanisms driving this conversion to cancer, we
developed a novel reporter of melanoma initiation in a zebrafish melanoma model (that relies on this same
BRAFV600E mutation) that expresses a fluorescent protein (EGFP) in the first cell of melanoma and can be
visualized in a live animal. Using this model, we found that embryonic neural crest identity reemerges during
melanoma initiation, and that regulation of sox10 neural crest transcription factor levels in melanocytes is one
key control point in this process.
 In this proposal, we will test the hypothesis that a specific subset of normally embryonic transcriptional
inputs modulates sox10 activity during melanoma initiation and that upregulation of neural crest transcription
factors -- in addition to and potentially upstream of sox10 -- directs this transition to malignancy. By defining the
role of key transcriptional inputs in modulating sox10 in its native context, we will understand the molecular
mechanisms modulating the melanocyte to melanoma transition. We further identify additional neural crest
transcription factors that may modulate this process and determine their role and regulation in melanoma
initiation. Finally, we use human melanoma patient-derived xenografts (PDX) to further clarify if ongoing
expression of these factors is needed for melanoma viability or if their role is primarily during tumor initiation.
Overall, this proposal describes innovative approaches to determine the precise regulation of altered
transcriptional and epigenetic programs driving melanoma cancer initiation, which may define new and earlier-
acting therapeutic targets for treating melanoma.

## Key facts

- **NIH application ID:** 10212983
- **Project number:** 5R01CA240633-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Charles Kore Kaufman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $360,751
- **Award type:** 5
- **Project period:** 2019-08-13 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212983

## Citation

> US National Institutes of Health, RePORTER application 10212983, Defining Transcriptional Regulators of Melanoma Initiation using Zebrafish (5R01CA240633-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10212983. Licensed CC0.

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