Project 2: Immune signals promoting pancreas cancer stemness and progression

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ABSTRACT (Project 2) There is an urgent need to discover improved therapies for pancreatic ductal adenocarcinoma (PDAC), which require a better understanding of mechanisms underlying development and recurrence. Chronic inflammation is a feature and an independent risk factor for PDAC. Interactions between immune cells, cancer associated fibroblasts (CAFs), and cancer cells can promote PDAC development and progression. However, little is known about how immune cells or immune cell-related signals affect PDAC development. Our long-term goal is to identify signaling nodes that facilitate the crosstalk between immune cells, cancer cells and CAFs to promote PDAC progression. In healthy subjects, IL-22 is expressed by immune cells while its receptor, IL- 22RA1, is selectively expressed in non-immune cells. IL-22 and IL-22RA1 expression are both elevated in PDAC, but little is known about the role of this signaling axis in PDAC. We have recently demonstrated high, heterogeneous expression of IL-22RA1 in human and mouse PDAC. Importantly, high IL-22RA1 expression is associated with poor prognosis of PDAC patients. Furthermore, we showed that IL-22RA1high cells in PDAC have cancer stem cell properties, including high tumorigenicity in vivo. We found that IL-22 stimulates IL- 22RA1 expression through STAT3 activation in PDAC cells, and postulate that this positive feedback loop enhances stemness and tumorigenicity of PDAC cancer cells. Thus, IL-22RA1/STAT3 signaling might provide a therapeutic target to treat PDAC with high IL-22RA1. We will use different mouse models of PDAC to study the effects of genetic deletion of IL-22RA1 in acinar cells or PSCs on PDAC growth, metastasis, and stemness in vivo. We will use novel, multi- dimensional analysis methods to analyze if inflammation drives carcinogenesis via IL-22, IL-22 expression in immune cell populations in PDAC mouse models and test therapeutic benefit of blocking IL-22 signaling in PDAC using pharmacologic and genetic approaches. We will determine the expression and role of IL-22/IL-22RA1 axis in human PDAC. Using primary human pancreatic ductal epithelial cells with defined PDAC genetic driver mutations, we will study the contribution and regulation of IL-22/IL-22RA1 signaling in human PDAC development. Our proposed studies will novel insights into how genetic drivers and inflammation orchestrate functional connection and communication between immune and non-immune components in PDAC. Further, we will gain mechanistic understanding of how (1) immune cell, CAF, and cancer cell interactions mediated by the IL-22/IL-22RA1 axis lead to PDAC development and (2) inhibition of the IL-22/IL-22RA1 signaling axis provides a therapeutic strategy that targets cancer stemness, a major factor in therapy resistance and the dismal prognosis associated with PDAC.