# Exploring the role of stromal GLI proteins in Pancreatic Ductal Adenocarcinoma

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $37,270

## Abstract

ABSTRACT
Pancreatic Ductal Adenocarcinoma (PDA) remains one of the deadliest cancers, with minimal therapeutic
improvement over the last 40 years. This lack of effective therapies is due, in part, to a poor understanding of
the signaling mechanisms driving PDA. Our lab and others have identified an aberrant increase in Hedgehog
(HH) ligand production during PDA progression that signals to the surrounding tumor stroma (Thayer and Pasca
di Magliano et al., 2003; Berman et al., 2003; Jones et al., 2008; Theunissen & de Sauvage, 2009). Disruption
of HH signaling influences PDA progression, although the exact effect is controversial. This controversy stems,
in part, from a poor understanding of the mechanisms mediating HH signaling in PDA. Prior research from our
lab has demonstrated that HH signaling restrains PDA tumor growth in a dose-dependent manner (Mathew et
al., 2014). However, the mechanisms that dictate the levels of HH signaling in PDA are poorly understood. In
development and other forms of HH-driven disease, the GLI family of HH transcription factors (GLI1, GLI2, GLI3)
plays a crucial role in mediating downstream HH signaling. However, the role of GLI1-3 in PDA remains largely
unknown. My data indicate that Gli1-3 are expressed in the healthy pancreas, and that this expression is
restricted to pancreatic fibroblasts. In addition, I have determined that the expression Gli1-3 expands throughout
the pancreatic stroma during the formation of precancerous lesions. Based on these preliminary data, I
hypothesize that GLI1-3 restrict PDA tumor growth by regulating stromal HH signaling. To test this
hypothesis, I will first determine the expression and protein processing of GLI1-3 in the context of metastatic
pancreatic cancer. I will also evaluate the expression of HH target genes at different stages of PDA progression,
to correlate GLI1-3 expression and processing with the level of HH pathway activity. To define the role of stromal
GLI proteins in PDA, I will eliminate Gli expression in pancreatic fibroblasts and determine the effect on
pancreatic cancer growth in situ. These experiments will provide mechanistic insight into our understanding of
HH signaling in PDA progression, and will reveal novel roles for GLI proteins in this deadly disease.

## Key facts

- **NIH application ID:** 9964490
- **Project number:** 5F31CA232655-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Michael Kemper Scales
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,270
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964490

## Citation

> US National Institutes of Health, RePORTER application 9964490, Exploring the role of stromal GLI proteins in Pancreatic Ductal Adenocarcinoma (5F31CA232655-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964490. Licensed CC0.

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