# Cell of Origin and the Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $451,616

## Abstract

Project Summary:
Neurofibromatosis type 1 (NF1) is a genetic disorder that affects around 1:3000 live births. While the disease
has nearly 100% penetrance in patients, NF1 has a diverse spectrum of manifestations. Hallmark traits of the
disease include café-au-lait macules, cutaneous neurofibromas (cNF), plexiform neurofibromas (pNF) and
malignant peripheral nerve sheath tumors (MPNST), among other symptoms. In NF1 patients, cNFs usually
arise at puberty and beyond, can range widely in size and number, and can cause itching, pain, superficial
infections as well as psychosocial and cosmetic burdens. Currently, there is no approved therapeutic option for
cNFs aside from elective surgery. The development of new therapeutic approaches for cNF will require an
understanding of the cNF cellular origin that can be used to elucidate mechanisms that underpin cNF formation
and growth. While biallelic inactivation of NF1 in neoplastic Schwann cells is essential for cNF formation, it is
not sufficient, pointing to the critical roles of other genetic or epigenetic changes as well as extrinsic signals
from other cell types in the tumor microenvironment. While the field has made significant inroads towards our
understanding of these tumors, there are still gaps in our knowledge of cNF pathogenesis that could be
addressed by the adoption of a systemic approach to decipher all the biological steps in cNF development from
the cell of origin to tumor stage to identify the “rate limiting step” that can be therapeutically targeted to prevent
or delay cNF formation. Therefore, in this application, we propose a set specific aims to fill this knowledge
gap: We will define the identity of the cNF cell of origin in mice that will guide us to identify the cells of origin for
human cNF. We will next decipher how the cell of origin and the tumor microenvironment contribute to drive
cNF initiation that will uncover its pathogenesis to delineate biological steps and mechanisms in tumor
development as well as generating of preclinical models system that elucidate cNF biology and enable
preclinical therapeutic testing.

## Key facts

- **NIH application ID:** 9978724
- **Project number:** 5R01CA166593-08
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Lu Le
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,616
- **Award type:** 5
- **Project period:** 2012-08-03 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978724

## Citation

> US National Institutes of Health, RePORTER application 9978724, Cell of Origin and the Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics (5R01CA166593-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978724. Licensed CC0.

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