# The role and regulation of Hippo pathway in sarcomagenesis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $368,288

## Abstract

Project Summary/Abstract
 Soft tissue sarcomas are an aggressive group of mesenchymal malignancies diagnosed in 200,000
people per year worldwide. Unlike in epithelial cancers, where novel targeted therapies have had a dramatic
effect on patient survival, the treatment approach for mesenchymal tumors including sarcomas has not
changed significantly in 25 years. Our recent work revealed that deregulation of the Hippo pathway enhances
sarcomagenesis in the aggressive muscle tumor, Undifferentiated pleomorphic sarcoma (UPS). UPS is a
commonly diagnosed and metastatic sarcoma subtype frequently found in adult muscle tissues. We have
observed that loss of Angiomotin (AMOT), a crucial mediator of Hippo-associated growth restriction, is required
for UPS sarcomagenesis. AMOT is highly expressed in differentiated human muscle tissue but is silenced in
UPS and other sarcomas. Ectopic re-expression of the p130 isoform of AMOT significantly inhibits sarcoma
cell proliferation in vitro. This finding is consistent with the only known function of AMOT in cancer cells, which
is to sequester the Hippo pathway effector YAP1 and facilitate its degradation. YAP1 is a pro-proliferation
transcriptional regulator whose deletion in an autochthonous mouse model of UPS significantly decreased
tumorigenesis. Together these data suggest that AMOT loss promotes YAP-mediated sarcomagenesis in
muscle-derived UPS. We next investigated the downstream effects of YAP1 expression in UPS by microarray
gene expression studies of control and Yap1-deficient murine tumors. We found that Yap1 controls NF-κB
signaling in UPS by suppressing expression of Usp31, a negative regulator of NF-κB activity. Furthermore,
using ChIP-seq of patient samples we found that NF-κB signaling is substantially upregulated in human UPS.
Consistent with these findings, UPS cell proliferation is highly sensitive to NF-κB inhibition. Based on these
findings in Specific Aim1 we will determine how AMOT loss is controlled in UPS and if this process is required
for tumor initiation in soft tissue sarcomas. Next we will define the mechanism by which YAP1 suppresses
USP31 expression in Specific Aim 2. We will investigate whether YAP1 directly binds to the promoter region
of USP31, preventing its transcription. Loss of YAP1 restores expression of USP31, a peptidase that removes
activation specific ubiquitin modifications from lysine 63 in TRAF molecules upstream of p65, thereby
inactivating NF-κB. The role of NF-κB in normal skeletal muscle progenitors, the putative cell of origin of UPS,
is to promote proliferation and prevent differentiation. In Specific Aim3 we will determine which YAP1-
dependent NF-κB targets are necessary for regulating either or both of these processes. The goal of this
proposal is to test the hypothesis that deregulated Hippo signaling promotes sarcomagenesis via suppression
of AMOT, resulting in YAP1/NF-κB-associated proliferation and inhibition of differentiation. Ultimately, the
purpose of ...

## Key facts

- **NIH application ID:** 9867707
- **Project number:** 5R01CA229688-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Tzipora Sarah Karin eisinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,288
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867707

## Citation

> US National Institutes of Health, RePORTER application 9867707, The role and regulation of Hippo pathway in sarcomagenesis (5R01CA229688-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9867707. Licensed CC0.

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