Abstract 2682: IL-6/STAT3 activation in hepatocytes drives the formation of a pro-metastatic niche in the liver during pancreatic tumorigenesis
Authors: Lee Jae W. , Porrett Paige M. , Komar Chad A. , Gladney Whitney L. , Beatty Gregory L. 
Published: July 2017

Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related deaths in the United States with metastasis to the liver as the major cause of mortality. While the propensity of PDAC to spread to the liver may reflect mechanical trapping of tumor cells that enter the portal circulation, primary tumor cells have also been suggested to secrete factors that may promote recruitment of myeloid cells to establish a pro-metastatic niche. In this study, we used the LSL-KrasG12D/+;LSL-Trp53R127H/+;Pdx-1-Cre (KPC) mouse model of PDAC to investigate the impact of PDAC development on the formation of a pro-metastatic niche in the liver. We found that KPC mice (compared to age- and gender-matched control mice) demonstrated an increased susceptibility to tumor seeding in the liver even prior to development of invasive PDAC. Examination of the liver of KPC mice revealed diffuse activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling, particularly in hepatocytes. Although hepatocytes are recognized as important regulators of inflammation, their role in establishing a pro-metastatic niche is unknown. To define changes in the liver associated with development of a pro-metastatic niche, we performed QuantSeq analysis on RNA isolated from the liver of KPC versus control PC mice. Our results showed increased transcriptional levels of myeloid chemoattractants, particularly serum amyloid A proteins that are predominantly produced by hepatocytes. Consistent with this finding, we observed an accumulation of F4/80+ and Ly6G+ myeloid cells in the liver of KPC mice by immunofluorescence microscopy. We next determined the role of tumor cells in driving cellular activation seen in the liver by establishing intraperitoneal and orthotopic models of PDAC. Using these models, we found that implantation of pancreatic tumor cells induced STAT3 activation in hepatocytes and stimulated F4/80+ and Ly6G+ myeloid cell recruitment to the liver. To determine whether cellular activation in the liver was associated with systemic release of soluble factors, we performed parabiotic joining of tumor-implanted mice and control wild type mice, and we found evidence of STAT3 activation and myeloid recruitment to the liver in parabiotic pairs. As interleukin-6 (IL-6) is a key inflammatory cytokine that can activate STAT3 signaling, we hypothesized a role for IL-6 directed STAT3 activation in hepatocytes for development of a pro-metastatic niche in the liver. Consistent with this hypothesis, we found that IL-6 receptor blocking antibodies administered after tumor implantation reduced STAT3 activation in hepatocytes and decreased transcriptional levels of hepatocyte-derived chemoattractants. Together, our findings support a role for IL-6/STAT3 signaling in hepatocytes in driving a pro-metastatic niche in the liver during PDAC development.

Citation Format: Jae W. Lee, Paige M. Porrett, Chad A. Komar, Whitney L. Gladney, Gregory L. Beatty. IL-6/STAT3 activation in hepatocytes drives the formation of a pro-metastatic niche in the liver during pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2682. doi:10.1158/1538-7445.AM2017-2682