Antonella Farsetti
Antonella Farsetti
affiliation: National Research Council of Italy - Institute of Cell Biology and Neurobiology
research area(s): Cancer Biology, Experimental Medicine
Course: Experimental Endocrinology, Metabolism and Endocrine Surgery
University/Istitution: Università Cattolica del Sacro Cuore

1986 Laurea in Medicine cum laude, University "La Sapienza", Rome, Italy.

1989 Board Certified in Endocrinology and Metabolism cum laude, University "La Sapienza", Rome, Italy.

1992 PhD in Molecular Endocrinology, University "La Sapienza", Rome, Italy.


1984-86 Student, Department of Experimental Medicine, Chair of Endocrinology, University "La Sapienza", Rome.

1986-88 Intern, Department of Experimental Medicine, Chair of Clinical Pathology, University "La Sapienza", Rome.

1988-1991 Fogarty Visiting Fellow, Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, MD, USA. Main research interests: Hormonal control of cerebral differentiation: thyroid hormone and thyroid receptors regulation of brain development.

1989-2000 Staff Scientist, Institute of Neurobiology and Molecular Medicine, National Research Council (CNR), Rome, Italy.

1991-1992 Fogarty Visiting Associate, Genetic and Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, MD, USA. Main research interests: Characterizationof the molecular mechanisms underlying active repression mediated by Thyroid Hormone Receptor splicing variant α2 (TRα2)

1993-today Group Leader, CNR Molecular Endocrinology and Oncology Unit and Regina Elena Cancer Institute, Department of Experimental Oncology, Rome, Italy. Current research interests: Molecular mechanisms underlying transcriptional regulation of sex steroid hormone receptors in the development and progression of human prostate cancer.

1995 Exchange Visiting Fellow, Genetics and Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, MD, USA. Main research interests: Transcriptional regulation of gene expression.

1996 N.A.T.O.-CNR Senior Fellow Genetics and Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, MD, USA. Main research interests: Estrogen receptor action and cross talk with other members of the Superfamily of Steroid/Thyroid Hormone Receptors.

1999 Visiting Professor, Department of Pathology and Molecular Medicine, McMaster University Medical Center, Hamilton, (ON) Canada. Research interest: Hormonal regulation of telomerase.

2001-today Senior Staff Scientist, Institute of Cell Biology and Neurobiology, National Research Council (CNR), Rome, Italy.

2004 Visiting Professor, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston (MA), USA. Research interests: Primary Cultures of Prostate Luminal Cells as a Model for an Integrated Approach to Prostate Cancer: Isolation, Characterization and Gene Profiling.

2006 Visiting Research Scholar, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston (MA), USA. Research interests: Hypoxia response signature as predictor of poor clinical outcome in PCa by Tissue Microarrays analysis.
Title: Targeting nuclear eNOS in aggressive prostate cancer
The gaseous molecule nitric oxide (NO) is the enzymatic product of a family of proteins known as Nitric Oxide Synthases (NOS) which are distinguished in endothelial, neuronal and inducible isoforms. NO plays important metabolic functions controlling the intracellular level of the second-messenger cyclic-GMP and in part that of cyclic-AMP through the direct regulation of Guanylate Cyclase (CG) function. Very recently NO and its synthases reached celebrity among oncologists because of the evidence of frequent dysregulation in NO production in several tumours, specifically in those hormone-dependent including prostate cancer.
Our discoveries that activation of the NO pathway represents a "primum movens" of a transcriptional program aimed at the acquisition of an aggressive phenotype in prostate cancer cells, and that the nuclear translocation of the endothelial NOS (eNOS) significantly affects chromatin remodelling of a specific subset of prognostic genes prompt us to investigate the full potentiality of this key signalling molecule as master gene in the progression of prostate cancer.
Specifically the goals of the current research activities coordinated by Dr. Farsetti are to characterize the novel role of nuclear eNOS and to identify its putative partners present in combinatorial complexes bound to chromatin and their relevance in the regulation of eNOS target genes.
Our working hypothesis is based on further observations from our laboratory on the functional role of nuclearized eNOS in both normal and tumour cells , i.e. human endothelial cells (Grasselli et al. Circ. Research 2008) and immortalized prostate cancer cells derived from epithelial primary cultures obtained from fresh PCa explants (Nanni et al.J. Clin. Invest. 2009). The evidence from these studies suggests that the eNOS activity is required for its nuclear functions specifically directed at changing the local chromatin environment.
The challenge is now to unmask the function of eNOS on a genome-wide scale. We expect to reveal a general mechanism associated with the presence of nuclear eNOS in PCa tumours. This possibility will be explored by Mass Spectrometry while the discovery of eNOS target genes will be attempted by ChIP-Sequencing. By this combined approach, newly eNOS partners might be identified having relevance for the design of novel therapeutical approaches. In this regard we plan to evaluate the role of newly identified eNOS partners and/or targets as diagnostic/prognostic tools by comparing data from TMAs and biopsy/surgery specimens, and by ChIP in vivo on fresh PCa tissues. This information may allow us to anticipate PCa clinical outcome already at the time of biopsy.
In light of the key importance of eNOS in tumor maintenance and progression, as well as in consideration of the common clinical use of NO donors, the present project may open a new area of research with important basic and clinical implications.
1 S Misiti, S Nanni, G Fontemaggi, Y Cong, J Wen, HW Hirte, G Piaggio, A Sacchi, A Pontecorvi, S Bacchetti, A Farsetti (2000) Induction of hTERT expression and of telomerase activity by ligand-dependent estrogen receptor a in human ovary epithelium cells. Mol.Cell.Biol.20:3764-71
2 S Nanni, M Narducci, L Della Pietra, F Moretti, A Grasselli, P De Carli, A Sacchi, A Pontecorvi, A Farsetti (2002) Signaling through Estrogen Receptors Modulates Telomerase Activity In Human Prostate Cancer. J.Clin.Invest.110:219-27
3 S Nanni, C Priolo, A Grasselli, M D'Eletto, R Merola, F Moretti, M Gallucci, P De Carli, S Sentinelli, AM Cianciulli, M Mottolese, P Carlini, D Arcelli, MH Citterich, C Gaetano, M Loda, A Pontecorvi, S Bacchetti, A Sacchi, A Farsetti (2006) Epithelial-restricted gene profile of primary cultures from human prostate tumors: a molecular approach to predict clinical behavior of prostate cancer. Mol.Cancer Res 4:79-92
4 ML Narducci, A Grasselli, LM Biasucci, A Farsetti, A Mulè, G Liuzzo, G Niccoli, R Mongiardo, A Pontecorvi and F Crea. (2007) High telomerase activity in neutrophils from unstable coronary plaque. J.American Coll. Cardiology. 50:2369-74
5 A Grasselli, S Nanni, C Colussi, A Aiello, V Benvenuti, G Ragone, F Moretti, A Sacchi, S Bacchetti, C Gaetano, M Capogrossi, A Pontecorvi, A Farsetti (2008) Estrogen Receptor alpha and Endothelial Nitric Oxide Synthase Nuclear Complex Regulates Transcription of Human Telomerase. Circ Res.103:34-42
6 U Moehren, M Papaioannou, C Reeb, A Grasselli, S Nanni, M Asim, A Farsetti, A Baniahmad. (2008) Wildtype but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development. Faseb Journal. 22:1258-67
7 S Nanni, V Benvenuti, A Grasselli, C Priolo, A Aiello, S Mattiussi, C Colussi, V Lirangi, B Illi, M D'Eletto, AM Cianciulli, M Gallucci, P De Carli, S Sentinelli, M Mottolese, P Carlini, L Strigari, S Finn, E Mueller, G Arcangeli, C Gaetano, MC Capogrossi, RP Donnorso, S Bacchetti, A Sacchi, A Pontecorvi, M Loda, A Farsetti (2009) Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J Clin Invest.119:1093-108
8 B Illi, C Colussi, A Grasselli, A Farsetti, MC Capogrossi, C Gaetano (2009) NO sparks off chromatin: tales of a multifaceted epigenetic regulator. Pharmacol Ther. 123:344-52.
9 C Priolo, M Agostini, N Vena, AH Ligon, M Fiorentino, E Shin, A Farsetti, A Pontecorvi, E Sicinska, M Loda. (2010) Establishment and genomic characterization of mouse xenografts of human primary prostate tumors. Am J Pathol.176:1901-13
10 J Rosati, F Spallotta, A Grasselli, A Antonini, S Vincentie, C Presutti, S Nanni, A Farsetti, MC Capogrossi, B Illi, C Gaetano. (2011) SIP-1 and MiRna 200 Family Define a Nitric Oxide-Dependent Molecular Circuitry Involved in Embryonic Stem Cells Vascular Differentiation. Arterioscler Thromb Vasc Biol.31:898-907
Project Title:
Genome-wide Analysis of eNOS-binding DNA Regions to Unmask Novel Regulatory Elements Important for Estrogen Transcriptional Response in Human Endothel
In prior work we identified eNOS as a nuclear co-factor of Estrogen Receptors  and  in different cellular contexts, i.e. endothelial and prostate cancer cells. To elucidate the nuclear role of eNOS and clarify its involvement in the basal and/or hormone-dependent transcriptional regulation, a genome-wide profiling, by Chromatin ImmunoPrecipitation/Sequencing (ChIP-Seq), of protein-DNA interacting sites will be performed in human endothelial cells after eNOS nuclear enrichment following estrogen stimulation. The goal of the project is to identify novel eNOS-bound “nuclear” partners.