Exploring the role of stromal GLI proteins in Pancreatic Ductal Adenocarcinoma

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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.