Anales RANF

S10-03 ROLE OF PURINERGIC SIGNALIN IN PANCREATIC CANCER I. Novak, R. Bouazzi R., L. Magni, H. Heredero Olmedilla, N. Christensen Department of Biology, University of Copenhagen, Copenhagen, Denmark Pancreatic ductal adenocarcinoma (PDAC) is rising in incidence and has very poor prognosis. New disease markers and therapeutic targets are urgently needed. Our knowledge of the genetics and epidemiology of the disease is on par with many other cancers, but the molecular mechanisms that give rise to PDAC are unresolved. Therefore, we seek better understanding of cellular/molecular mechanisms involved in cross-talk between fibrogenic pancreatic stellate cells (PSC) and cancer cells. Chemical factors within the tumor microenvironment that mya play significant roles are extracellular acid, nucleotides/sides, cytokines and hypoxia. Our studies aim to elucidate whether purinergic signaling is an important determinant of tumor development/progression. Our study on mouse cancer model indicated that the P2X7 receptor (P2X7R) contributes to fibrosis and cancer progression (1). Therefore, we aimed to clarify mechanisms by which P2 receptors, in particular P2X7R, contribute to PSC-cancer cell cross- talk. We found that human and murine PSCs express P2X7R, which stimulates collagen secretion and cell proliferation, and these can be targeted by e.g. AZ10606120. Moreover, P2X7R also regulates secretion of IL-6, which promotes PDAC cell migration and cancer development. In PDAC cells, P2X7R also stimulates migration, while in PSCs it is the P2Y2 receptor that regulates cell migration. Extracellular ATP sources in the tumor are from metabolically active PDAC cells, as well as mechanosensitive PSC. Further stimuli of ATP release are bile acids and extracellular acid load, which are important factors in inflammation and pancreatitis, conditions associated with promoting pancreatic cancer development. Our studies show that therapeutic targeting of purinergic signaling between pancreatic stellate cells and pancreatic cancer cells may be a promising avenue for co-/therapy of pancreatic cancer. 1. Giannuzzo et al. J Cancer 139, 2540, 2016. Supported by The Danish Council for Independent Research (DFF 4002-00162 and DFF 8020-00254B) and EU Talent Ph.D. Grant.