# Targeting the Cancer Stem Cells in Malignant Peripheral Nerve Sheath Tumor

> **NIH NIH R37** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $356,850

## Abstract

Project Summary
Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcomas deeply associated with
nerves. The clinical observation and mouse model studies indicate the vital role of the nerve microenvironment
in MPNST tumorigenesis, but the mechanism is still not clear. Our recent data showed a stem-like tumor cell
population in both primary human MPNST and MPNST mouse models. The cancer stem cell (CSC) population
in mouse MPNSTs can be labeled by a transgene that was also expressed in the neural crest stem cell, the
cell-of-origin of NF1-associated tumors. The CSCs demonstrated significantly high potentials to generate new
tumors in sciatic nerve transplantation and the metastases by intracardiac injection. The nerve-enriched tumor
microenvironment and the consistent high ERBB3 expression between neural crest stem cells and CSCs
strongly suggest the neuregulin1 (NRG1)-ERBB3 signaling, which regulates early Schwann cell lineage
development, can contribute to the tumor initiation. CD44 facilitates the ERBB2 and ERBB3 heterodimer
formation and promotes the downstream focal adhesion kinase, boosting the metastatic phenotype.
Interestingly, the CD44 can be upregulated through loss of function of TP53 and activated ERK signaling that
are also the two critical determinants for MPNST malignant progression. Therefore, we will test the central
hypothesis that targeting the NRG1-ERBB3-CD44 positive feedback loop can inhibit tumor initiation and CSC-
related metastasis. Using a novel transgenic mouse model and humanized MPNST models, we will pursue
three aims 1) To test the hypothesis that disruption of the NRG1-ERBB3-CD44 loop blocks MPNST growth and
progression. 2) To test whether hyaluronan-CD44-PAK2 signaling is critical for MPNST CSC-initiated
metastatic seeding and growth. 3) To evaluate the therapeutic potential of targeting the ERBB3-CD44 axis
combined with ERK inhibition on humanized MPNST models. We expect the 1) ERBB3-targeted treatment will
inhibit the tumor growth, 2) CD44-targeted treatment can attenuate the CSC-induced metastasis, and 3) we
can prove the principle of therapeutic effects on MPNST xenograft models and through combination with MEK
inhibitor to suppress the single-drug induced resistance. These discoveries may fill the gap in MPNST
tumorigenesis and metastasis and pave the path for innovative translational study and clinical application.

## Key facts

- **NIH application ID:** 10513266
- **Project number:** 1R37CA274352-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Daochun Sun
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $356,850
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513266

## Citation

> US National Institutes of Health, RePORTER application 10513266, Targeting the Cancer Stem Cells in Malignant Peripheral Nerve Sheath Tumor (1R37CA274352-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10513266. Licensed CC0.

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