The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling, and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.

No abstract

No abstract

The differentiation of acinar cells to ductal cells during pancreatitis and in the early development of pancreatic cancer is a key process that requires further study. To understand the mechanisms regulating acinar-to-ductal metaplasia (ADM), ex vivo 3D culture and differentiation of primary acinar cells to ductal cells offers many advantages over other systems. With the technique herein, modulation of protein expression is simple and quick, requiring only one day to isolate, stimulate or virally infect, and begin culturing primary acinar cells to investigate the ADM process. In contrast to using basement membrane matrix, the seeding of acinar cell clusters in collagen I extracellular matrix, allows acinar cells to retain their acinar identity before manipulation. This is vital when testing the contribution of various components to the induction of ADM. Not only are the effects of cytokines or other ectopically administered factors testable through this technique, but the contribution of common mutations, increased protein expression, or knockdown of protein expression is testable via viral infection of primary acinar cells, using adenoviral or lentiviral vectors. Moreover, cells can be re-isolated from collagen or basement membrane matrix at the endpoint and analyzed for protein expression.

No abstract

No abstract

No abstract

Recent studies demonstrate that mitochondrially-generated reactive oxygen species (ROS) downstream of oncogenic KRAS drive acinar-to-ductal metaplasia (ADM), a key first step in the pancreatic ductal adenocarcinoma (PDA) progression model. MnSOD/SOD2 is a mitochondrial enzyme that converts superoxide into hydrogen peroxide. Previous studies have shown that SOD2 is biologically relevant to the study of pancreatic cancer. Some patients with a SOD2 polymorphism resulting in less active MnSOD at the mitochondrial matrix are at increased risk of developing pancreatic cancer. Additionally, MnSOD is lost in high-grade human PanIN, further suggesting a role in tumor development. To elucidate the role of MnSOD in pancreatic cancer initiation and progression, we crossed Sod2lox/lox mice into the p48Cre;LSL-KrasG12D (KC) mouse model. We found increased ROS, abundantly more abnormal tissue development and presence of flat lesions indicating accelerated early progression. However, Kaplan Meyer survival analysis of KC and KC;Sod2−/− mice did not indicate faster progression to cancer, suggesting that for later steps additional signaling is needed. In summary, we identify MnSOD as a key antioxidant molecule preventing initiation of PDA. Citation Format: Alicia K. Fleming Martinez, Brandy H. Edenfield, Irene Esposito, Peter Storz. Knockout of Sod2 accelerates KrasG12D-driven formation of pancreatic cancerous lesions. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4775.