Linking metabolic rewiring and chemoresistance in human pancreatic cancer
Background Pancreatic ductal adenocarcinoma, commonly referred to as pancreatic cancer (PC), has an extremely poor prognosis with an average median survival of only 6 months. PC is the 4th most frequent cause of cancer-related death globally. In Norway, an estimated 800 people die of PC each year, which is more than of breast cancer. Over the past decades, therapeutic advancement in treating PC has been negligible, profound resistance to any form of established therapy remaining the main obstacle to improved survival. Given the heavy individual and societal burden of PC, there is an urgent need for better therapeutics. PC is unique in that it contains abundant stroma, i.e. fibrous tissue that surrounds the cancer cells. The stiff stroma compresses the blood vessels inside the tumor, which leads to low oxygen and nutrient availability to the cancer cells, who have in fact a high metabolic demand in order to main cell proliferation and tumor growth. Emerging evidence indicates that under such challenging conditions, the cancer cells get help from neighboring pancreatic stellate cells (PSCs) - the major non-cancer cell type in the tumor microenvironment - to acquire nutrients through unconventional ways, a process called metabolic rewiring. Results from our recent study comparing the proteome of treatment-naïve PCs and PCs that have undergone (neoadjuvant) chemotherapy indicate that the maximum number of differentially regulated proteins belongs to metabolic pathways (unpublished data). Furthermore, it is known that PSCs are key to acquired chemoresistance in PC. However, how the metabolic interactions between PSCs and cancer cells are linked to chemoresistance is currently unknown.
Aim To explore the effects of the interactions between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) on the metabolism and chemosensitivity of PCCs, and to identify pathways that link both processes.
Methods The thesis work involves handling of six paired human pancreatic tumor-derived primary cultures of PCCs and PSCs, preparation of conditioned medium and assessment of its effects on proteome of PCCs and PSCs (proteome profiling), assessment of response to chemotherapeutic agents, and measurement of cellular metabolism. Relevant techniques for this study include cell culturing, spectrophotometry, immunocytochemistry, fluorescence microscopy, biochemical assays, ELISA, seahorse XF analyzer for measurement of changes in cellular energy/metabolism, protein extraction and western blot analysis. Proteome profiling using liquid chromatography-mass spectroscopy (LCMS/MS) will be performed in collaboration with core facilities at UiO.
Project group This thesis relates to multiple other ongoing projects embedded in the multidisciplinary research group “Pancreatic Cancer Biology and Therapeutics” led by Prof. Ivar P. Gladhaug at UiO, Norway. The primary focus of the team has been the investigation of the role of the tumor stroma in pancreatic cancer progression and the characterization of cancer-stroma interactions using human PDAC-derived biomaterials. The project group has laboratory facilities at the Department of Pharmacology, Institute of Clinical Medicine, UiO, Norway (location: OUS, Rikshospitalet). The state-of-the art methods to be used in this project are well established. More information can be provided upon request.
Project leader Prof. Caroline S. Verbeke, MD PhD Department of Pathology, University of Oslo, Norway Email: firstname.lastname@example.org
Project supervisor Dr. Manoj Amrutkar, MSc PhD Department of Hepato-Pancreato-Biliary Surgery, University of Oslo, Norway Email: email@example.com