Systems Pharmacology and Translational Therapeutics

Principal Investigator: Paola Patrignani (Full Professor), E-mail: ppatrignani@unich.it (CV)

Research activity description: Dr. Paola Patrignani, Full Professor of Pharmacology at "G. d’Annunzio" University, heads the Laboratory of Systems Pharmacology and Translational Therapeutics (SPaTT Lab). Dr. Patrignani is one of the “Top Italian Women Scientists" (https://www.ondaosservatorio.it/ondauploads/2017/06/TIWS-aggiornato-2020.pdf) and was the winner of the International Aspirin Foundation Senior Science Award 2018. The interest of the laboratory focuses on the study of eicosanoids in cardiovascular and cancer biology with interdisciplinary and translational approaches. Prof. Patrignani’s laboratory has long utilized mass spectrometry, initially to target the arachidonate derived lipidome, but more recently also the proteome. The mission of Patrignani’s lab is to clarify mechanisms of action, drug-drug interactions, and determinants of variability in the responses to antithrombotic agents, including antiplatelet drugs and non-vitamin K antagonist oral anticoagulants (NOACs). Using a proteomic technique for assessing platelet COX-1 acetylation, she discovered that the coadministration of statins counteracts the reduced bioavailability of Aspirin detected in some individuals with cardiovascular disease via the interference with aspirin extrusion protein (MRP4) (Figure 1). Her recent work is on the clarification of the role of platelets in the development of cancer.  Her group showed that platelets interact with cancer cells in the bloodstream and induce a genetic program of malignancy named epithelial-mesenchymal transition (EMT) (Figure 2). Circulating platelets can also acquire a specific phenotype in a patient by up taking plasma molecules, such as growth factors and RNA species (Figure 2). Thus, the assessment of platelet content (the proteome and transcriptome) has the potential of diagnostic utility and drug monitoring. This hypothesis will be verified in two clinical studies granted by AIRC and Cancer Research UK.  Moreover, these studies aim to develop novel biomarkers to predict the anticancer effects and possible side-effects of Aspirin

• Bruno A, Contursi A, Tacconelli S, Sacco A, Hofling U, Mucci M, Lamolinara A, Del Pizzo F, Ballerini P, Di Gregorio P, Yu Y, Patrignani P. The specific deletion of cyclooxygenase-1 in megakaryocytes/platelets reduces intestinal polyposis in ApcMin/+ mice. Pharmacol Res. 2022; 185: 106506.
• Hofling U, Tacconelli S, Contursi A, Bruno A, Mucci M, Ballerini P, Cohen S, Patrignani P. Characterization of the acetylation of cyclooxygenase-isozymes and targeted lipidomics of eicosanoids in serum and colon cancer cells by the new Aspirin formulation IP1867B versus Aspirin in vitro. Frontiers in Pharmacology 2022;13:1070277
• Contursi A, Fullone R, Szklanna-Koszalinska P, Marcone S, Lanuti P, Taus F, Meneguzzi A, Turri G, Dovizio M, Bruno A, Pedrazzani C, Tacconelli S, Marchisio M, Ballerini P, Minuz P, Maguire P, Patrignani P. Tumor-Educated Platelet Extracellular Vesicles: Proteomic Profiling and Crosstalk with Colorectal Cancer Cells. Cancers (Basel). 2023;15(2):350.
• D'Agostino I, Tacconelli S, Bruno A, Contursi A, Mucci L, Hu X, Xie Y, Chakraborty R, Jain K, Sacco A, Zucchelli M, Landolfi R, Dovizio M, Falcone L, Ballerini P, Hwa J, Patrignani P. Low-dose Aspirin prevents hypertension and cardiac fibrosis when thromboxane A2 is unrestrained. Pharmacol Res. 2021;170:105744. doi: 10.1016/j.phrs.2021.105744
• Contursi A, Schiavone S, Dovizio M, Hinz C, Fullone R, Tacconelli S, Tyrrell VJ, Grande R, Lanuti P, Marchisio M, Zucchelli M, Ballerini P, Lanas A, O’Donnell VB, Patrignani P. Platelets induce free and phospholipid-esterified 12-HETE generation in colon cancer cells by delivering 12-lipoxygenase. J Lipid Res 2021;100109. doi: 10.1016/j.jlr.2021.100109
• Balduini A, Fava C, Di Buduo CA, Abbonante V, Meneguzzi A, Soprano PM, Taus F, Castelli M, Giontella A, Dovizio M, Tacconelli S, Patrignani P, Minuz P. Expression and functional characterization of the large-conductance calcium and voltage-activated potassium channel Kca 1.1 in megakaryocytes and platelets. J Thromb Haemost. 2021. doi: 10.1111/jth.15269.
• Alberti S, Zhang Q, D'Agostino I, Bruno A, Tacconelli S, Contursi A, Guarnieri S, Dovizio M, Falcone L, Ballerini P, Münch G, Yu Y, Patrignani P. The antiplatelet agent revacept prevents the increase of systemic thromboxane A2 biosynthesis and neointima hyperplasia. Sci Rep. 2020;10(1):21420.
• Tacconelli S, Fullone R, Dovizio M, Pizzicoli G, Marschler S, Bruno A, Zucchelli M, Contursi A, Ballerini P, Patrignani P. Pharmacological characterization of the biosynthesis of prostanoids and hydroxyeicosatetraenoic acids in human whole blood and platelets by targeted chiral lipidomics analysis. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865(12):158804. doi: 10.1016/j.bbalip.2020.158804.
• Tacconelli S, Contursi A, Falcone L, Mucci M, D'Agostino I, Fullone R, Sacco A, Zucchelli M, Bruno A, Ballerini P, Dovizio M, Patrignani P. Characterization of cyclooxygenase-2 acetylation and prostanoid inhibition by aspirin in cellular systems. Biochem Pharmacol. 2020; 178:114094. doi: 10.1016/j.bcp.2020.114094.
• Sacco A, Bruno A, Contursi A, Dovizio M, Tacconelli S, Ricciotti E, Guillem-Llobat P, Salvatore T, Di Francesco L, Fullone R, Ballerini P, Arena V, Alberti S, Liu G, Gong Y, Sgambato A, Patrono C, FitzGerald GA, Yu Y, Patrignani P. Platelet-Specific Deletion of Cyclooxygenase-1 Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice. J Pharmacol Exp Ther. 2019;370(3):416-426. doi: 10.1124/jpet.119.259382
• Saul MJ, Baumann I, Bruno A, Emmerich AC, Wellstein J, Ottinger SM, Contursi A, Dovizio M, Donnini S, Tacconelli S, Raouf J, Idborg H, Stein S, Korotkova M, Savai R, Terzuoli E, Sala G, Seeger W, Jakobsson PJ, Patrignani P, Suess B, Steinhilber D. miR-574-5p as RNA decoy for CUGBP1 stimulates human lung tumor growth by mPGES-1 induction. FASEB J. 2019;33(6):6933-6947. doi: 10.1096/fj.201802547R
• Renda G, Ricci F, Patti G, Aung N, Petersen SE, Gallina S, Hamrefors V, Melander O, Sutton R, Engstrom G, Caterina R, Fedorowski A. CHA2DS2VASc score and adverse outcomes in middle-aged individuals without atrial fibrillation. Eur J Prev Cardiol. 2019;26(18):1987-1997. doi: 10.1177/2047487319868320
• Tacconelli S, Dovizio M, Di Francesco L, Meneguzzi A, D'Agostino I, Evangelista V, Manarini S, Capone ML, Grossi L, Porreca E, Di Febbo C, Bruno A, Ballerini P, Levantesi G, Fava C, Minuz P, Patrignani P. Reduced variability to aspirin antiplatelet effect by the coadministration of statins in high-risk patients for cardiovascular disease. Clin Pharmacol Ther. 2018; 104(1): 111-119. doi: 10.1002/cpt.1075
• Renda G, Ricci F, Giugliano RP, De Caterina R. Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease. J Am Coll Cardiol 2017;69(11):1363-1371. doi: 10.1016/j.jacc.2016.12.038
• Patrignani P, Sacco A, Sostres C, Bruno A, Dovizio M, Piazuelo E, Di Francesco L, Contursi A, Zucchelli M, Schiavone S, Tacconelli S, Patrono C, Lanas A. Low-dose aspirin acetylates cyclooxygenase-1 in human colorectal mucosa: implications for the chemoprevention of colorectal cancer. Clin Pharmacol Ther. 2017;102(1):52-61. doi: 10.1002/cpt.639
• Patrignani P, Patrono C. Aspirin and Cancer. J Am Coll Cardiol. 2016;68(9):967-76.
• Guillem-Llobat P, Dovizio M, Bruno A, Ricciotti E, Cufino V, Sacco A, Grande R, Alberti S,  Arena V, Cirillo M, Patrono C, FitzGerald GA, Steinhilber D, Sgambato A, Patrignani P. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget. 2016;7(22):32462-77. doi: 10.18632/oncotarget.8655
• Di Francesco L, Dovizio M, Trenti A, Marcantoni E, Moore A, O'Gaora P, McCarthy C, Tacconelli S, Bruno A, Alberti S, Gizzo S, Nardelli GB, Orso G, Belton O, Trevisi L, Dixon DA, Patrignani P. Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells. Br J Pharmacol. 2015; 172(18): 4575–4587. doi: 10.1111/bph.13241
• Xiao B, Gu SM, Li MJ, Li J, Tao B, Wang Y, Wang Y, Zuo S, Shen Y, Yu Y, Chen D, Chen G, Kong D, Tang J, Liu Q, Chen DR, Liu Y, Alberti S, Dovizio M, Landolfi R, Mucci L, Miao PZ, Gao P, Zhu DL, Wang J, Li B, Patrignani P, Yu Y. Rare SNP rs12731181 in the miR-590-3p Target Site of the Prostaglandin F2α Receptor Gene Confers Risk for Essential Hypertension in the Han Chinese Population. Arterioscler Thromb Vasc Biol. 2015;35:1687-95. doi: 10.1161/ATVBAHA.115.305445
• Olesch C, Sha W, Angioni C, Sha LK, Açaf E, Patrignani P, Jakobsson PJ, Radeke HH, Grösch S, Geisslinger G, von Knethen A, Weigert A, Brüne B. MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer. Oncotarget. 2015;6(12):10284-96. Doi: 10.18632/oncotarget.3581
• Dovizio M, Maier TJ, Alberti S, Di Francesco L, Marcantoni E, Münch G, John CM, Suess B, Sgambato A, Steinhilber D, Patrignani P. Pharmacological inhibition of platelet-tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Mol Pharmacol. 2013;84(1):25-40. doi: 10.1124/mol.113.084988
• Tang WH, Stitham J, Gleim S, Di Febbo C, Porreca E, Fava C, Tacconelli S, Capone M, Evangelista V, Levantesi G, Wen L, Martin K, Minuz P, Rade J, Patrignani P, Hwa J. Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane. J Clin Invest. 2011; 121(11): 4462-76. doi: 10.1172/JCI59291.
• Di Francesco L, Totani L, Dovizio M, Piccoli A, Di Francesco A, Salvatore T, Pandolfi A, Evangelista V, Dercho RA, Seta F, Patrignani P. Induction of prostacyclin by steady laminar shear stress suppresses tumor necrosis factor-alpha biosynthesis via heme oxygenase-1 in human endothelial cells. Circ Res. 2009; 104(4): 506-13. doi: 10.1161/CIRCRESAHA.108.191114
• García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol. 2008;52(20):1628-36. doi: 10.1016/j.jacc.2008.08.041
• Evangelista V, Manarini S, Di Santo A, Capone ML, Ricciotti E, Di Francesco L, Tacconelli S, Sacchetti A, D'Angelo S, Scilimati A, Sciulli MG, Patrignani P.  De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res. 2006; 98(5): 593-5. doi: 10.1161/01.RES.0000214553.37930.3e
• Patrignani P, Di Febbo C, Tacconelli S, Moretta V, Baccante G, Sciulli MG, Ricciotti E, Capone ML, Antonucci I, Guglielmi MD, Stuppia L, Porreca E. Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo. Blood. 2006; 107(9): 3572-4. doi: 10.1182/blood-2005-12-4811
• Renda G, Tacconelli S, Capone ML, Sacchetta D, Santarelli F, Sciulli MG, Zimarino M, Grana M, D'Amelio E, Zurro M, Price TS, Patrono C, De Caterina R, Patrignani P. Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease. Clin Pharmacol Ther. 2006; 80(3): 264-74. doi: 10.1016/j.clpt.2006.05.004
• Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol. 2005; 45(8): 1295-301. doi: 10.1016/j.jacc.2005.01.045
• Patrignani P, Panara MR, Greco A, Fusco O, Natoli C, Iacobelli S, Cipollone F, Ganci A, Créminon C, Maclouf J, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther. 1994;271(3):1705-12.
• Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982; 69(6): 1366-72. doi: 10.1172/jci110576