Abstract 3920: nfP2X7 mediates survival of cancer cells in the tumor microenvironment

Abstract

Abstract The purpose of this study was to demonstrate the effect of the tumor microenvironment (TME) on expression of nfP2X7, a cancer specific form of P2X7 involved in cancer cell survival. P2X7 is an ATP-gated receptor, involved in inflammation, cell death, cell proliferation and cell migration. Alterations in these cellular processes are associated with the development of cancer. P2X7 is characterized by its capacity to open a large molecular weight pore in response to prolonged ATP activation. A mechanism that triggers membrane depolarisation and cell death. The TME contains high concentrations of ATP sufficient to cause opening of the P2X7 pore, while ATP is almost undetectable in healthy tissue. Secretion by cancer cells and release of intracellular ATP from dying cells are thought to be the main source of extracellular ATP in the TME. Non-functional P2X7 (nfP2X7) is a cancer-specific receptor in which formation of the large molecular weight pore, has been abrogated. Acquisition of nfP2X7 enables tumor cells to survive in the presence of high ATP concentrations. Using antibodies raised against nfP2X7, we assessed the expression of the receptor in a panel of cancer types and analysed the effect of the high ATP concentrations on nfP2X7 expression. We further analyzed the effect of siRNA mediated nfP2X7 depletion on cancer cell lines' viability. Our data shows that nfP2X7 is broadly expressed at the surface of many cancer types and supports cancer cell survival. Furthermore, we demonstrate that exposure to a high ATP concentration, equivalent to those in the TME, drives nfP2X7 expression. These data demonstrate that nfP2X7 is a cancer therapeutic target, whose expression is driven by the TME. Citation Format: Simon Mark Gilbert, Christopher John Oliphant, Anne-Lise Peille, Peter Bronsert, Francesco Di Virgilio, Shaun McNulty, Romain Lara. nfP2X7 mediates survival of cancer cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3920.