Abstract 1982: Sustained CXCR2 signaling promotes secretory phenotype in cancer-associated fibroblasts of pancreatic cancer via activation of NFkB (2019)

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the US and remains one of the most challenging malignancies. Desmoplasia and tumor-supporting inflammation are hallmarks of PC. In addition to the autonomous aggressiveness feature of PC malignant cells, host tumor microenvironment contribute greatly to tumor progression and spread. Cancer-associated fibroblasts (CAFs), represent the major component of the tumor microenvironment in PC, are implicated in facilitating therapy resistance and metastasis. Recent reports emphasize the concurrence of multiple subtypes of CAFs that carry out different functions. CXCR2 is a chemokine receptor that is known for its role during inflammation by recruiting innate immune cells and the induction of angiogenesis. In PC, oncogenic Kras upregulates CXCR2 and its ligands (CXCL1-3 and 5-8), which are linked to inducing tumor proliferation and immunosuppression as well as induction of malignant cells stemness contributing to therapy resistance. Deletion of CXCR2 in a syngeneic mouse model (Cxcr2-/-) of PC increased the abundance of fibrosis revealing a potential undescribed role of CXCR2 in regulating CAFs. We hypothesize that CXCR2 regulates CAFs function in PC and contribute to CAFs heterogeneity. Co-culture of PC tumor cells in the conditioned media of CAFs and co-culturing CAFs in conditioned media of tumor cells revealed an oncogenic Kras-dependent interaction. CAFs enhanced the growth of PC cells with oncogenic Kras; whereas, conditioned media of the PC cells with oncogenic Kras has inhibited CAFs growth. Paracrine factors derived from tumor cells decreased the expression of the fibrotic CAFs-associated markers including αSMA and collagen I, and increased the expression of immunosuppressive cytokines and tumor-promoting chemokines including IL-4, IL-10, IL-13 and CXCL7. Utilizing recombinant CXCR2 chemokines and CXCR2 inhibitors, we confirmed the involvement of CXCR2 in this secretory phenotype. CXCL1 and CXCL8 exhibited a similar effect on CAFs by downregulating αSMA and upregulating IL-4, IL-13 and CXCL7. CXCR2 inhibitors reverted some of the observed effects. Examining downstream signaling pathways revealed that this effect is mediated through activation of NFκB. We further confirmed these findings in-vivo. Immunohistochemistry revealed higher αSMA expression in the tumors implanted in Cxcr2-/- compared to wildtype mice. Altogether, we demonstrate that sustained signaling through CXCR2 activates NFκB and induces a secretory phenotype of CAFs in PC that upregulates pro-tumor immunosuppression growth factors.Citation Format: Mohammad Awaji, Michelle Varney, Abhilasha Purohit, Lingyun Wu, Sugandha Saxena, Sushil Kumar, Surinder K. Batra, Rakesh K. Singh. Sustained CXCR2 signaling promotes secretory phenotype in cancer-associated fibroblasts of pancreatic cancer via activation of NFkB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1982.