Abstract B27: Interdicting the cytokine-mediated paracrine communication between pancreatic cancer and stellate cells as a new treatment approach for pancreatic ductal adenocarcinoma

Abstract

Abstract Cell-cell interactions within the tumor microenvironment play critical roles in tumor progression and its response to various therapies. Specifically in the case of pancreatic cancer, pancreatic cancer cells (PCCs) act on pancreatic stellate cells (PSCs), a major stromal cell type within the pancreatic tumor microenvironment, to provoke their transformation into and sustain an activated state, while activated PSCs interact with PCCs to promote tumor progression and confer a favorable environment for PCC resistance to immunosuppression and therapeutic treatment, setting up a vicious cycle. Therefore, effectively attacking the stromal PSCs alone or together with tumor cells may offer a new therapeutic route for pancreatic ductal adenocarcinoma (PDA) treatment. To identify key signaling molecules or pathways activated as a result of PSC-PCC interactions that might be targeted in pancreatic cancer as novel therapies, we developed unbiased quantitative mass spectrometry (MS)-based proteomics strategies to perform systemic analysis. Our comprehensive molecular and cellular analysis of in vitro PSC and PSC co-culture unraveled many interesting secreted proteins, either known or unknown previously, involved in the paracrine PCC-PSC crosstalk. We mainly focused on an intriguing signaling loop, in which PCCs secrete PDGFs that act on PSCs to promote the production of inflammatory cytokines by PSCs, including IL-6 family members, and especially LIF. These cytokines then act on PCCs to stimulate STAT3 activation, a known critical event for PDA initiation and progression. Significantly increased production of the cytokines and expression of corresponding receptors in both mouse and human PDA tumor contexts at both mRNA and protein levels were confirmed using various techniques. To further evaluate the functional significance of LIF in paracrine regulation of PDA progression in vivo, we exploited therapeutic blockage of the signaling using neutralizing mAbs and specific small molecule inhibitors in the classical KPC mouse PDA model. Our preclinical studies revealed significant efficacy of an anti-LIF mAb in increasing sensitivity to the standard-of-care chemotherapeutic gemcitabine, reducing tumor progression and prolonging survival of KPC mice. Currently, the molecular mechanisms underlying this sensitization are being investigated. Genetic studies using LIF receptor conditional knockout mice were also performed and showed significant beneficial effects. Furthermore, potential correlations between tissue or serum LIF and IL-6 cytokine levels and overall survival of human patients are also being evaluated. Citation Format: Yu Shi, Ruijun Tian, Tony Hunter.{Authors}. Interdicting the cytokine-mediated paracrine communication between pancreatic cancer and stellate cells as a new treatment approach for pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B27.