Abstract 4208: Suppressor of Cytokine Signaling (SOCS)-3 and the C-X-C chemokines CXCL1 and CXCL2 promote tumor aggessiveness and radiation resistance in pancreatic cancer

Abstract

Abstract Despite recent advances in our understanding of pancreatic ductal adenocarcinoma (PDA), it remains a poorly understood, devastating disease that is largely resistant to all standard treatment modalities. Much effort has been made to identify novel tumor suppressor genes, biomarkers of metastatic behavior, and targets for molecular therapeutics that can improve prognosis and quality of life for PDA patients. Despite the finding that the pro-inflammatory C-X-C family chemokines CXCL1 and CXCL2 are expressed in a significant fraction of human PDA tissues and are known to promote metastasis in bladder and breast cancer, very little is known of its regulation and its role in the progression of PDA. Our laboratory has identified a mechanism by which CXCL1 expression is regulated in human PDA. CXCL1/2 expression is repressed by the Signal Transducer and Activator of Transcription (STAT)-3 and conversely, the Suppressor of Cytokine Signaling (SOCS)-3, a STAT3 inhibitor, promotes CXCL1/2 gene activation and pro-inflammatory signaling in murine embryonic fibroblasts (MEFs) and human PDA cell lines. Ectopic expression of SOCS3 in the ASPC1 PDA cell line induces CXCL1 and CXCL2 expression and drives resistance to radiation and gemcitibine treatment. Further, using an orthotopic xenograft model of human PDA in immunodeficient mice, we demonstrated the in vivo relevance of this pathway. We found that mice injected with human SOCS3-positive human PDA cells have a survival time compared and develop more aggressive disease compared to mice injected with control cells. We hypothesize that CXCL1and CXCL2 promote human PDA pathogenesis by two mechanisms: (i) autocrine activation of the CXCR2 receptor expressed on human pancreatic cancer cells and (ii) pro-inflammatory recruitment of neutrophils to the tumor microenvironment. Citation Format: Sisi Jiang, Evangeline Mose, Giovanni Coppola, Andrew Lowy, Christina Jamieson, Nicholas A. Cacalano. Suppressor of Cytokine Signaling (SOCS)-3 and the C-X-C chemokines CXCL1 and CXCL2 promote tumor aggessiveness and radiation resistance in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4208. doi:10.1158/1538-7445.AM2014-4208