autophagy level via enhancing SREBP1 expression. Moreover, activation of autophagy accelerated SREBP1 expression and suppressed apoptosis. In high glucose mice model, tumor growth was promoted. Conclusion: High glucose microenvironment promoted pancreatic cancer growth and suppressed autophagy via upregulating SREBP1 both in vitro and in vivo. SREBP1 may represent a novel target for pancreatic cancer prevention and treatment. P7-57. Molecular mechanisms of sonoporation in pancreatic ductal adenocarcinoma (PDAC) Ragnhild Haugse 1, 2 , Anika Langer 1 , Silje Maria Sundøy 1 , Spiros Kotopoulis 3, 4, 5 , Emmet McCormack 6 1 University of Bergen, Department of Clinical Science, Bergen, Norway 2 Hospital Pharmacy in Western Norway, Bergen, Norway 3 Phoenix Solutions AS, Oslo, Norway 4 University of Bergen, Department of Clinical Medicine, Bergen, Norway 5 Haukeland University Hospital, National Centre for Ultrasound in Gastroenterology, Bergen, Norway 6 University of Bergen, Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Bergen, Norway Background and Objectives: The use of ultrasound and microbubbles to enhance therapeutic efficacy is commonly known as sonoporation. Sonoporation has been found to enhance the efficacy of chemotherapy both preclinically and in a Phase I clinical trial in pancreatic ductal adenocarcinoma. The primary mechanism of sonoporation has typically been defined as the formation of transient pores in cell membranes caused by the ultrasound itself, or by the microbubbles excited by ul- trasound. The main hypothesis for the improved treatment efficacy is that the formation of pores in the cell membrane allows for enhanced drug uptake. The exact mechanisms leading to improvement in therapy is however not clearly understood, and there is limited knowledge on the intracellular mechanisms following sonoporation. In other cells types we have found that several intracellular signalling pathways are in fact changed upon sonoporation, and the effects are primarily seen in cancer cells and not healthy cells. In this study the primary aim was to investi- gate the intracellular signalling response following sonoporation in pancreatic cancer cells. Materials and Methods: The MIAPACA-2 cell line and fibroblasts were treated at different levels of ultrasound intensity with and without microbubbles (Sonazoid™) using a custom-made plate sonicator. Cells were cultured and sonoporated in low-oxygen transfer cell culture chambers (Petaka G3 LOT ® ) to mimic hypoxic in vivo intratumoral condi- tions. Flow cytometry and western blots was used to elucidate the phos- phorylation status of intracellular proteins immediately and two hours after treatment. Results: The treatment with ultrasound and microbubbles (sonopo- ration) changes intracellular signaling in proteins and pathways relevant for cancer therapy in pancreatic cancer cells, like MAPKinase, focal adhe- sion kinase (FAK) and ribosomal protein S6. Conclusion: The results suggest that sonoporation has effects on cancer cells by itself, besides increased drug delivery, which may be relevant for therapy in PDAC. Combining sonoporation with inhibitors of these pathways may result in a novel molecular targeted therapy where ultrasound could be the localized activation trigger. P7-58. Mitochondria as a potential target for cadmium toxicity in the development of pancreatic cancer David Wallace 1 , Vladimir Djordjevic 2 , Aleksandra Buha Djordjevic 3 1 Oklahoma State Univ Ctr for Health Sci, Pharmacology, Tulsa, United States 2 First Surgical Clinic, Clinical Center of Serbia, Belgrade, Serbia 3 University of Belgrade-Faculty of Pharmacy, Toxicology, Belgrade, Serbia Background and Objectives: Pancreatic cancer (PC) is an insidious cancer with a high mortality rate due to late-stage detection. Many envi- ronmental factors have been postulated to be ‘causes’ for PC, and we have targeted the actions of cadmium (Cd). Of particular interest is the potential ability of Cd to interfere with normal mitochondrial function and changes in apoptotic pathways. Mitochondrial involvement in PC development is becoming accepted, and exposure to Cd is suspected of being a risk factor for PC development, yet the mechanism is unclear. These early studies examine the role of Cd as a mitochondrial toxicant and if alterations in mitochondrial function may be an underlying cause for the development of PC. Materials and Methods: CdCl 2 -mediated toxicity in HPNE and AsPC-1 pancreatic cell lines was determined by measuring the release of LDH and generation of free radicals. Mitochondrial toxicity assays were performed in media containing glucose (25 mM) or galactose (10 mM) and exposure to CdCl 2 (0-100 mM) followed by MTT staining. For confirmation of mito- chondrial toxicity, we measured the release of ATP following exposure to CdCl 2 . The principle of the mitochondrial toxicity tests is that substituting 10 mM galactose for 25 mM glucose shifts the cell from oxidative phos- phorylation to aerobic glycolysis and will increase susceptibility to mito- chondrial toxins. Results: CdCl 2 -mediated mito-tox effects were larger in HPNE cells suggesting greater sensitivity to CdCl 2 not due to elevated oxidative stress. There was a significant effect of media on IC 50 values (F 1,44 ¼25.38; P<0.0001) observed in both cell lines. HPNE-galactose IC 50 values were significantly (P<0.001) lower than in the HPNE-glucose group. Increased mito-tox sensitivity was indicated by a 73.4% reduction in IC 50 values in galactose compared to glucose media in HPNE cells, whereas AsPC-1 cells exhibited a 58.8% reduction in IC 50 values. Also, the higher concentration of CdCl 2 elicited a significant cell-dependent effect on ATP release in both cell lines, suggestive of CdCl 2 being a mitochondrial toxicant. Conclusion: Cell survival was unaffected following low-level CdCl 2 exposure, but exposure did alter mitochondrial function (control cells > tumor cells). The IC 50 shift suggests that CdCl 2 does act as a mitochondrial toxin in both HPNE and AsPC-1 cells, with more robust responses observed in control cells. Thus, mitochondria may be a site for CdCl 2 -mediated tu- mor development. P7-59. Aldh1a3 labels a subtype of cancer-associated fibroblasts with inflammatory phenotype in pancreatic ductal adenocarcinoma Jing Cao, Zhiheng Zhang, Carsten J€ ager, Helmut Friess, Bo Kong Klinikum rechts der Isar, Technical University of Munich, Department of Surgery, Munich, Germany Background and Objectives: Cancer-associated fibroblasts (CAFs) are considered as an essential component of the tumour microenvironment. Due to its heterogeneity in pancreatic ductal adenocarcinoma (PDAC), the exact role of CAFs is controversially discussed. Aldh1a3, a member of aldehyde dehydrogenases subfamily 1, is a well-established marker for stem/progenitor cells. In this study, we investigated the role of Aldh1a3- positive CAFs in PDAC. Materials and Methods: Immunohistochemistry analysis was per- formed to localize the ALDH1A3-positive cells in human tissue sections of PDAC and chronic pancreatitis. Kaplan-Meier survival analysis was per- formed to interrogate the impact of ALDH1A3-positive cells on patients’ survival. We generated an inducible Cre knock-in line on murine Aldh1a3 locus to map the tissue-resident Aldh1a3-positive cells. A 3D co-culture Abstracts / Pancreatology 19 (2019) S1eS180 S164