Su1909 Microtubule Dependent Recognition of Intracellular Microbial Nucleic Acids

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is a frequent and lethal disease ranking fourth as a cause of cancer-related death in Western countries. PDAC is characterized by an intense desmoplastic stroma, due to the activation of pancreatic stellate cells. Our group has shown that pancreatic cancer progression can be restrained via modulation of the stellate cells in the stroma. The treatment of stellate cells in an in vitro and an in vivo PDAC model with an isoform of retinoic acid (ATRA) rendered these cells quiescent, and affected Wnt-β-catenin signaling pathway, slowing down tumor progression. In the in vivo model, it was also shown that CD8+ T cells were able to infiltrate into the juxtatumoural compartment of PDAC in mice treated with ATRA. The aim of this work is to assess if combined treatment with ATRA (targeting stellate cells), and chemotherapeutic agent Gemcitabine (targeting cancer cells) has a synergistic detrimental effect on pancreatic cancer progression. Methods Organotypic cultures (OT) were constructed to mimic human PDAC, and were treated according to human chemotherapy regimen cycles. Furthermore KPC (LSLKrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice were treated with the combination of Gemcitabine and ATRA. Appropriate controls were used for both in vivo and in vitro assays with drug alone or vehicle alone to be able to differentiate between the effects of individual drugs. Both the in vivo and in vitro assays were studied for various surrogate endpoints for chemotherapy efficacy. Results In the organotypic model, ATRA alone or in combination with Gemcitabine reduced cancer and stellate cells invasion. Stellate cell activation was significantly reduced upon combination treatment withGem/ATRA, in comparison to cultures treated with Gem or ATRA only. In the KPC mice model, ATRA alone or in combination with Gemcitabine caused stromal collapse in KPC mice, which led to an increased vascular density in the tumor area and a reduction in tumour volume, when compared with mice treated with ATRA or gemcitabine alone. Further assessments are being carried out. Conclusions The combination treatment of ATRA and Gemcitabine may have a synergistic detrimental effect upon pancreatic cancer progression.