Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths with 5-year survivals below 10%. Cancer stem cells represent a small population of cells in PDAC and are thought to drive the development, progression, metastasis and drug resistance of this cancer. The Notch pathway regulates the self-renewal of pancreatic cancer stem cells as well as angiogenesis and drug resistance. Gamma-secretase cleaves the Notch-1 receptor, resulting in release of the Notch intracellular domain (NICD) that then translocates to the nucleus and activates the transcription of target genes. Aberrant Notch signaling activated by γ-secretase activity is associated with progression, angiogenesis and drug resistance of PDAC and is being explored as a target for PDAC therapy. Smoking and psychological stress are risk factors for PDAC. However, the potential modulation of γ-secretase/Notch by these risk factors has not been investigated to date. Nicotine and psychological stress both cause hyperactivity of the sympathetic nervous system and adrenal glands, resulting in increased blood and organ levels of the stress neurotransmitters norepinephrine (NOR) and epinephrine (EPI), which are the physiological agonists of beta-adrenergic receptors (β-ARs). In turn, β-ARs are coupled to the stimulatory G-protein Gαs that stimulates the formation of intracellular cAMP, which activates multiple signaling pathways in a cell type-specific manner. Using spheroid formation assays and Western blotting, our data show, -for the first time,- that the stress neurotransmitter Epi significantly increases the self-renewal of pancreatic cancer stem cells by increasing the expression of the activated forms (c-terminal) of the γ-secretase component presenilin1 and of Notch1 (NICD). These responses were inhibited by the β-AR antagonist (beta-blocker) propranolol and by the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that inhibits cAMP formation via activation of Gαi-coupled GABAB receptors. These findings suggest that the γ-sexretasesecretase/Notch pathway in pancreatic cancer stem cells is under regulatory control by neurotransmitters, with Epi as stimulator and GABA as inhibitor. These data could open up new avenues for the prevention and therapy of PDAC. Additional experiments are currently underway to further investigate mechanistic aspects of this novel concept. Supported by RO1CA042829 with NIH.

Note: This abstract was not presented at the meeting.

Citation Format: Xuemin Xu, Chen Hu, Hildegard M. Schuller. Epinephrine-induced gamma-secretase/Notch signaling in pancreatic cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2894. doi:10.1158/1538-7445.AM2017-2894