# To study the molecular oncogenesis of congenital Neurocutaneous melanocytosis in a preclinical transgenic mouse model

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $75,665

## Abstract

PROJECT SUMMARY: Neurocutaneous Melanocytosis (NCM) is a rare congenital disorder characterized by
benign to aggressively malignant pigmented lesions in the brain and melanocytic nevi on skin present at birth.
Incidence is estimated at 1/50,000 – 1/200,000 births. Symptomatic NCM, reported to be a third to half of all
cases is fatal, death occurring within 2-3 years of diagnosis due to neurological and other abnormalities. Due to
the rarity of human samples and unavailability of experimental models, very little is known about the origin and
development of the disease. Recently, somatic activating mutations in NRAS (NRAS Q61K/R) have been
identified in majority of NCM patients’ tumors (Kinsler et.al., 2013). Mutation acquired early during development
in the embryonic neural crest cells (NCCs) is thought to be the driving factor. However, nothing is known about
the molecular mechanisms underlying NRAS activation in NCCs and oncogenic processes involved in their
neoplastic transformation. Our preliminary data indicate that NRAS Q61K expression in NCCs is not sufficient to
initiate tumorigenesis in a transgenic mouse. Additional evidence suggests that Hepatocyte Growth Factor (HGF)
signaling during embryogenesis may be an important component in driving leptomeningeal and skin
melanocytosis. This proposal aims to test the hypothesis that mitogenic signaling from overactive HGF plays a
cooperative role in initiating neoplastic transformation of NRAS Q61K/R mutant NCCs during development. Two
different transgenic mice – one conditionally expressing NRAS Q61K in developing NCCs and the other
described by Glenn Merlino’s laboratory as overexpressing HGF during embryogenesis will be used to develop
a transgenic mouse model of NCM. Lesions developed in the offspring resultant from cross breeding these two
transgenic variants will be characterized using histological analyses, fluorescence IVIS imaging and MRI. To
identify the molecular determinants of NCCs transformation RNA-Sequencing approaches along with differential
gene expression analysis, pathway analysis and immunohistochemical methods will be employed. From these
data, this study aims to elucidate the cellular pathways involved in the origin and progression of NCM, induced
cooperatively by oncogenic NRAS and HGF. These experiments fit the mission of the NIH and NCI because
they have direct relevance to furthering our understanding of the mechanisms underlying the development of a
rare pediatric cancer about which we know very little. Furthermore, they develop a transgenic mouse model as
an experimental platform to investigate cooperative factors in NRAS initiated oncogenesis from NCCs and will
serve as useful in vivo paradigm for understanding molecular underpinnings of NRAS driven tumors of neural
crest derived tissues in future studies.

## Key facts

- **NIH application ID:** 10814293
- **Project number:** 5R03CA280130-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Dipanjan Basu
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,665
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814293

## Citation

> US National Institutes of Health, RePORTER application 10814293, To study the molecular oncogenesis of congenital Neurocutaneous melanocytosis in a preclinical transgenic mouse model (5R03CA280130-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814293. Licensed CC0.

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