Abstract
Abstract Background: Pancreatic cancer (PC) has consistently been the fourth cancer-related cause of death in United States for more than 10 years. Its dismal prognosis is due to the aggressive behavior, late detection, lack of reliable biomarkers and low response to chemotherapy. Obesity, characterized by high levels of leptin, correlates to low PC survival. Notch and leptin signaling have been associated with increased tumor growth and chemoresistance. We have previously shown that leptin induces proliferation of PC cell lines, increases Notch expression, PC stem cells (PCSC) and tumorsphere formation. Hypothesis: Leptin increases PC chemoresistance through its crosstalk to Notch signaling pathway that is essential for the expansion of PCSC. Methods: To test whether a leptin-Notch crosstalk axis is involved in PC-chemoresistance, human PC (MiaPaCa-2, Panc-1 and BxPC-3) cells were cultured in serum-free medium containing leptin, Gemcitabine and 5-Fluorouracil (5-FU) in combination with DAPT (γ-secretase inhibitor) and leptin signaling inhibitor bound to iron-oxide nanoparticles (IONP-LPrA2). PC cells were cultured with leptin and allow to form primary and secondary tumorspheres, enriched in PCSC. Tumorspheres were treated with the compounds described for 7-14 days. Number and size of tumorspheres were recorded, and expression of leptin receptor, OB-R and secretion of leptin were determined by Western blot (WB) and ELISA, respectively. Additionally, the levels of Notch, PCSC and EMT markers, pluripotency associated genes (Oct-4, Sox-2 and Nanog) and ATP-binding cassette transporters (ABCB1, ABCG2 and ABCC5) were determined using flow cytometry and WB. Results: PC cells expressed Leptin/OB-R system, suggesting an autocrine role in PC progression and chemoresistance. Leptin induced the formation of primary and secondary tumorspheres and increased their expression of Notch, EMT and pluripotency markers. Additionally, chemotherapeutics induced PC survival and the expression of ATP-binding cassette transporters in tumorspheres that was reinforced by leptin actions. Blockade of leptin signaling via IONP-LPrA2 and Notch activation via DAPT reduced leptin-induced molecular effects, PCSC and tumorsphere growth. Conclusion: Present data suggest that obesity, through leptin-induced Notch signaling, could increase chemoresistance in PC patients. Inhibition of leptin-Notch axis may be novel therapeutic strategy for PC, which may improve chemotherapeutic efficacy and increase survival in PC patients, particularly in obese contexts. Acknowledgements: this work has been supported by a Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR 03034 and 1C06 RR18386). Citation Format: Adriana Harbuzariu, Crystal C. Lipsey, Ruben R. Gonzalez-Perez. Leptin-Notch crosstalk axis: A novel target for pancreatic cancer [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 3544. doi:10.1158/1538-7445.AM2017-3544
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