# Pathogenic mechanisms of sinonasal sarcoma, a novel gender dimorphic cancer

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $205,700

## Abstract

PROJECT SUMMARY
 Bi-phenotypic sinonasal sarcoma (SNS) is a newly identified sarcoma that affects women three times more
frequently than men. The only treatment for this highly invasive lesion is disfiguring facial surgery. We recently
identified a novel fusion in SNS, which creates a novel chimera PAX3-MAML3 that fuses the DNA-binding
domain of the PAX3 transcription factor with the Mastermind-like 3 (MAML3) transcriptional co-activator. The
transcriptional program that PAX3-MAML3 triggers to elicit malignant transformation and invasive growth, and
the basis of the gender dimorphism of SNS is completely uncharacterized. Preliminary data demonstrate that
expression of PAX3-MAML3 is sufficient to drive formation of tumors that histologically mimic SNS, and to
induce gene expression patterns observed in SNS. Notably, PAX3-MAML3 induced expression of estrogen
receptor β (ERβ) and phosphorylation of ERα, and stimulated ER activity. Furthermore, tumors formed by
xenografted PAX3-MAML3-expressing cells were significantly larger in female than male recipient mice.
Transcriptome analysis of primary SNS tumors confirmed activation of an estrogen response signature in vivo.
These results lead us to hypothesize that the ER plays an essential role in PAX3-MAML3's pathogenic activity
in SNS, and that this underlies the gender dimorphic nature of this cancer. We further posit that anti-
estrogens might serve as a complementary or even alternative approach to disfiguring surgery for the
treatment of this highly invasive cancer. This will be tested through the following: Aim I: Determine role of
ER in PAX3-MAML3 pathogenesis in vitro and in vivo We will examine the effects of ER inactivation, using
CRISPR and anti-estrogenic agents (i.e. tamoxifen, fulvestrant, and aromatase inhibitor), on multiple aspects
of PAX3-MAML3-induced transformation: (A) In vitro, we will monitor effects on cell proliferation and survival,
anchorage-independent growth, and invasiveness. (B) In vivo, we will test the contribution of ER and estrogen
signaling to PAX3-MAML3-mediated tumorigenesis. We will assess the effects of ER inactivation (by CRISPR-
mediated depletion of ERα/ERβ or by treatment of mice with anti-estrogenic agents), comparing tumor growth
in male vs. female mice. Aim II: Determine how PAX3-MAML3 and ER coordinate gene expression to
drive invasive growth We will: (A) define the transcriptional program induced by PAX3-MAML3 by RNA-seq,
and determine how it is modulated by ER (through use of ER agonists, and CRISPR-mediated deletion of
ERα/β); and (B) define the PAX3-MAML3 and ER chromatin occupancy landscapes to gain a mechanistic
understanding of how PAX3-MAML3 and ER coordinate this transcriptional program. Transcriptome and ChIP-
seq data sets will be intersected to distinguish direct from indirect target genes of PAX3-MAML3 and ER, and
to gain insight into cooperative effects on transcription. A longterm goal of this integrated analysis is to facilitate
identificati...

## Key facts

- **NIH application ID:** 10089419
- **Project number:** 5R21CA234829-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Margaret Mary Chou
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $205,700
- **Award type:** 5
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089419

## Citation

> US National Institutes of Health, RePORTER application 10089419, Pathogenic mechanisms of sinonasal sarcoma, a novel gender dimorphic cancer (5R21CA234829-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10089419. Licensed CC0.

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