Guido Serini, born May 13, 1968 1987: Torino (Italy), Liceo Ginnasio Valsalice, High School (Lyceum) Diploma. 1989-1992: Torino (Italy), Dept. of Biomedical Sciences and Human Oncology, University of Torino School of Medicine, Prof. P. M. Comoglio's lab, predoctoral training in cellular and molecular biology. 1992-1993: Torino (Italy), Section of Internal Medicine of San Luigi Gonzaga Hospital, University of Torino School of Medicine, Head: Prof. Alberto Angeli, clinical training in internal medicine. Oct. 1993: Torino (Italy), University of Torino School of Medicine, M.D. summa cum laude, discussing a thesis about the "Overexpression of the MET oncogene in thyroid carcinomas: correlation with biological, histomorphological and clinical prognostic factors" (Tutors: Prof. Alberto Angeli and Prof. P. M. Comoglio). Oct.1998: Torino (Italy), Dept. of Biomedical Sciences and Human Oncology, University of Torino School of Medicine, Ph.D. in Human Oncology, (Tutor: Prof. P.C. Marchisio), discussing a thesis about the "Cancer development in the context of extracellular matrix and stromal cells: integrins and their ligands as downstream effectors of cytokines". Employment and research experience: From Oct. 1993 to Sept. 1994 Position: Research Fellow Institution: Molecular Histology Unit, Dept. of Biological and Technological Research, San Raffaele Scientific Institute – Milano, Italy. Head: Prof. Pier Carlo Marchisio. Research topic: Expression and function of cell adhesion molecules and extracellular matrix proteins in normal and neoplastic thyroid tissues. From Oct. 1994 to Dec. 1997 Position: Research Assistant Institution: Dept. of Pathology, Centre Médical Universitaire (CMU), University of Geneva School of Medicine – Geneva, Switzerland. Head: Prof. Giulio Gabbiani. Research topic: Mechanisms of induction of myofibroblasts by TGF: role of the alternatively spliced and TGF inducible extradomain A (ED-A) of cellular fibronectin. From Jan. 1998 to Dec. 1998 Position: Research Assistant Institution: Molecular Histology Unit, Dept. of Biological and Technological Research, San Raffaele Scientific Institute – Milano, Italy. Head: Prof. Pier Carlo Marchisio. Research topic: Growth Factor driven integrin adhesiveness in a human system of thyroid clonal strains derived from normal and papillary carcinoma. From Jan. 1999 to Dec. 2000 Position: Research Associate Institution: Division of Molecular Angiogenesis, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo, Italy. Head: Prof. Federico Bussolino. Research topic: Role of autocrine VEGF signaling in capillary network formation. From Jan. 2001 to Sept. 2005 Position: Senior Research Associate Institution: Division of Molecular Angiogenesis, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo, Italy. Research topic: Role of semaphorins in vascular development. 1 From Oct. 2005 to present Position: Assistant Professor of Clinical Biochemistry and Molecular Biology Institution: Department of Oncological Sciences, University of Torino School of Medicine, c/o Institute for Cancer Research and Treatment, Candiolo, Italy. Research topic: Mechanisms of regulation of integrin function in physiological and pathological angiogenesis. From Jan. 2009 to present Position: Head of the Laboratory of Cell Adhesion Dynamics Institution: Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo, Italy. Research topic: Mechanisms of regulation of integrin function in physiological and pathological angiogenesis. Scientific achievements: The PI has been studying the role of integrins and ECM in tumor progression and angiogenesis since 1993, after receiving his M.D. degree. Over the last ten years, the PI’s group made substantial contributions to the characterization of the molecular mechanisms that regulate the function of integrins in cancer cells, tumor-associated myofibroblasts, and endothelial cells (ECs). According to the ISI Web of Science from 1995 to 2010, the PI published 48 peer-reviewed papers, with 1785 total citations (37.19 average citations/item; 111.56 average citations/year) and an h-index of 20. • In 1996, working with Pier Carlo Marchisio (San Raffaele Scientific Institute, Milano), he firstly reported α6β4 integrin neo-expression as a hallmark of transition from benign adenomas to malignant carcinomas in humans, suggesting an important role for this integrin in the biology of human carcinomas (Serini et al., J. Natl. Cancer Inst. 1996; 88:442- 44). This manuscript has been cited 76 times. There is now a wide consensus on the pro-invasive function of α6β4 integrin in carcinomas (Giancotti, Nat. Rev. Mol. Cell Biol. 2004;5:816-826). • Working in Giulio Gabbiani’s lab (University of Geneva, Switzerland) he found (Serini et al., J. Cell Biol. 1998;142:873-881) that TGF-β activation of stromal cells into myofibroblasts, which play pro-invasive and pro-angiogenic roles in cancer (Orimo et al., Cell 2005;121:335-348), require a permissive integrin-driven signaling triggered from the alternatively spliced EDA domain of fibronectin. This manuscript has been cited 255 times. • In 1998, working with Pier Carlo Marchisio and Livio Trusolino(San Raffaele Scientific Institute, Milano), he showed for the first time (Trusolino, Serini et al., J. Cell Biol. 1998;142:1145-1156) that a growth factor (HGF) activates integrin function in epithelial cells and that this phenomenon is crucial for cancer progression. This manuscript has been cited 72 times. This observation has been extended to angiogenic growth factors and ECs (Byzova et al., Mol. Cell 2000;6:851–860) and there is now evidence that this is a general phenomenon (ffrench-Constant et al., Trends Cell Biol. 2004;14:678-686). • In 1999-2000, working with Federico Bussolino at the IRCC, he analyzed the mechanisms by which ECs self-assemble into a vascular network on Matrigel ECM, and found that autocrine VEGF secretion by ECs is critical for in vitro vascular network formation (Serini et al., EMBO J., 2003; 22:1771-1779). This manuscript has been cited 87 times. Later, it has been shown by others that endothelial VEGF autocrine loops are necessary also in vivo for solid tumor angiogenesis and cancer growth (Tang et al., Cancer Cell, 2004; 6:485-495). • In 2003, the PI’s group firstly showed that autocrine loops of class 3 semaphorin regulate vascular morphogenesis by inhibiting integrin function (Serini* et al., Nature 2003; 424:391-397 *Corresponding author). This article was commented in the “News and Views” by Patrick Mehlen (Nature 2003; 424:381-382). It is now clear that different semaphorins act by regulating integrin function in several cell types and that autocrine loops are also present in epithelial cells and lost during tumor progression 2 (Kruger et al., Nat. Rev. Mol. Cell Biol. 2005; 6:789-800). As extensively recognized by the scientific community over the years (Potiron & Roche, Sci. STKE. 2005(285):pe24; Halloran & Wolman, Curr. Opin. Cell Biol. 2006; 18:533-540; Neufeld & Kessler, Nat. Rev. Cancer 2008; 8:632-645; Lodish et al., Molecular Cell Biology, p. 1048, Sixth edition, W.H. Freeman & Co., New York, 2008; Jackson & Eickholt, Curr. Biol. 2009; 18:533-540), this was the first demonstration that the semaphorin/plexin signaling is central for the regulation of integrin function and vice versa. This manuscript has been cited 252 times. • In 2005, working together with the physicist Andrea Gamba (now head of the Systems Biology laboratory of the IRCC) he provided evidence that a PTEN/PIP2-driven phase transition could be the key mechanism by which eukaryotic cells amplify shallow chemoattractant gradients (Gamba et al., Proc. Natl. Acad Sci. USA 2005; 102:16927-16932). This article was commented as an “Editors’ choice” of the Signal Transduction Knowledge Environment of Science [Sci. STKE, now Science Signaling (Sci. STKE, Vol. 2005, Issue 312, pp. tw421, 29 November 2005. URL: http://stke.sciencemag.org/cgi/content/abstract/sigtrans; 2005/312/tw421)]. The same journal invited Dr. Serini and colleagues to submit a “Protocol” manuscript concerning the in silico analysis of the phase transition mechanisms supporting cell chemotaxis (A. de Candia, A. Gamba, F. Cavalli, A. Coniglio, S. Di Talia, F. Bussolino, and G. Serini. A simulation environment for directional sensing as a phase separation process. Sci. STKE, 2007, 378:pl1). • In 2009, the PI’s group uncovered that neuropilin 1 (Nrp1), independently from VEGF-A and SEMA3, supports EC adhesion to fibronectin by promoting the fast vesicular traffic of active α5β1 integrin back and forth from cell-to-extracellular matrix (ECM) contacts (Valdembri et al., PloS Biol. 2009, 7(1): e1000025; cited 26 times in 2 years). This was the first demonstration that: i) active integrin traffic is required for cell adhesion and spreading as well as for ECM polymerization; ii) active and inactive integrin traffic impinges upon molecularly different machineries. Therefore, during vascular morphogenesis real-time modulation of EC–to–ECM adhesion can result from two interconnected phenomena, namely the regulation of integrin conformation and traffic. It is likely that such an integrin treadmill could act as a major regulator of cell adhesion in general. This article has been recommended by two members (Richard Klemke and Arthur Mercurio) of the Faculty of 1000 Biology (Faculty of 1000 Biology: evaluations for Valdembri D et al PLoS Biol 2009 Jan 27 7 (1) :e25 http://www.f1000biology.com/article/id/1147951/evaluation). 3 Trained Ph.D. students: Donatella Valdembri, now Research Associate in my group at IRCC. Giulia Morterra, now working at Applied Biosystems. Luca Zammataro, now Bioinformatician at the Department of Translational Medicine, University of Milano, IRCCS Istituto Clinico Humanitas, Rozzano, Milano. Sara Zanivan. After having completed her M.Sci. and Ph.D. with me, she became a post-doc in Matthias Mann’s lab (Max-Planck Institute for Biochemistry, Martinsried, Germany) and is now junior group leader of the Vascular Proteomics lab, Beatson Institute for Cancer Research, Glasgow, UK (http://www.beatson.gla.ac.uk/Regulation-of-Cancer-Cell-Proliferation-and-Growth/Sara-ZanivanProteomics.html). Honors and awards: 2004: Young Researcher Award, Guido Berlucchi Foundation for Cancer Research, Borgonato di Corte Franca, Brescia, Italy (http://www.fondazioneberlucchi.com/). 2010: Associate Faculty Member, Faculty of 1000 Biology. (http://f1000biology.com/about/biography/4122053051167588) 2010: Editorial Board Member, Biology of the Cell. (http://www.biolcell.org) 2011: Editorial Board Member, Current Angiogenesis. (http://www.benthamscience.com/cag/index.htm) Publications: Articles 1. M.F. Di Renzo, M. Olivero, G. Serini, F. Orlandi, S. Pilotti, A. Belfiore, A. Costantino, R. Vigneri, A. Angeli, M.A. Pierotti and P.M. Comoglio. Overexpression of the c-Met/HGF receptor in human thyroid carcinomas derived from the follicular epithelium. J. Endocrinol. Invest. 1995;18: 134-139. 2. G. Serini, L. Trusolino, E. Saggiorato, O. Cremona, M. De Rossi, A. Angeli, F. Orlandi and P.C. Marchisio. Changes in integrin and E-cadherin expression in neoplastic versus normal thyroid tissue. J. Natl. Cancer Inst. 1996; 88: 442-449. 3. G. Serini and G. Gabbiani. Modulation of -smooth muscle actin expression in fibroblasts by transforming growth factor- isoforms: an in vivo and in vitro study. Wound Rep. Reg. 1996; 4: 278287. 4. M.T. Carlevato, L. Trusolino, G. Serini, G. Valente, F. Orlandi, A. Angeli, G. Cortesina and P.C. Marchisio. Differential integrin expression in thyroid and laryngeal carcinomas. Anticancer Res. 1996;16: 2379-2384. 5. G. Serini, M.L. Bochaton-Piallat, P. Ropraz, A. Geinoz, L. Borsi, L. Zardi, and G. Gabbiani. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by Transforming Growth Factor-1. .J. Cell Biol. 1998; 142: 873-881. 4 6. L. Trusolino, G. Serini, G. Cecchini, C. Besati, F.S. Ambesi Impiombato, P.C. Marchisio, and R. De Filippi. Growth factor-dependent activation of v3 integrin in normal epithelial cells: Implications for tumor progression. J. Cell Biol. 1998; 142: 1145-1156. 7. G. Serini. Loss of E-cadherin tyrosine phosphorylation in human cancers. Mol. Med. Today 1999; 5: 336. Letter. 8. G. Serini and G. Gabbiani. Mechanisms of myofibroblast activity and phenotypic modulation. Exp. Cell Res. 1999; 250: 273-283. Review. 9. F. Bussolino, S. Mitola, G. Serini, G. Barillari, and B. Ensoli. Interactions between endothelial cells and HIV-1. Int. J. Biochem. Cell Biol. 2001; 33: 371-390. 10. F. Bussolino, G. Serini, S. Mitola, G. Bazzoni, and E. Dejana. Dynamic modules and heterogeneity of function: a lesson form tyrosine kinase receptors in endothelial cells. EMBO Reports, 2001; 2:763767. 11. D. Valdembri, G. Serini , A. Vacca, D. Ribatti, and F. Bussolino. In vivo activation of JAK2/STAT-3 pathway during angiogenesis induced by GM-CSF. FASEB J. 2002; 16:225-227. 12. A. Gamba, D. Ambrosi, A. Coniglio, A. de Candia, S. Di Talia, E. Giraudo, G. Serini, L. Preziosi, and F. Bussolino. Percolation, Morphogenesis, and Burgers Dynamics in Blood Vessels Formation. Phys. Rev. Lett. 2003; 90: 118101. 13. G. Serini, D. Ambrosi, E. Giraudo, A. Gamba, L. Preziosi, and F. Bussolino. Modeling the early stages of vascular network assembly. EMBO J., 2003; 22: 1771-1779. 14. I. Cascone, E. Audero, E. Giraudo, L. Napione, F. Maniero, M.R. Philips, J. Collard, G. Serini, and F. Bussolino. Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1. Blood 2003, 102: 2482-2490. 15. G. Serini1, V. Valdembri, S. Zanivan, G. Morterra, C. Burkhardt, F. Caccavari, L. Zammataro, L. Primo, L. Tamagnone, M. Logan, M. Tessier-Lavigne, M. Taniguchi, A.W. Püschel, and F. Bussolino. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 2003, 424: 391397. 1Corresponding Author 16. I. Cascone, E. Audero, E. Giraudo, L. Napione, F. Maniero, M.R. Philips, J. Collard, G. Serini, and F. Bussolino. Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1. Blood 2003, 102: 2482-2490. 17. I. Cascone, E. Giraudo, F. Caccavari, L. Napione, E. Bertotti, J.G. Collard, G. Serini, and F. Bussolino. Temporal and spatial modulation of Rho GTPases during in vitro formation of capillary vascular network. Adherens junctions and myosin light chain as targets of Rac1 and RhoA. J. Biol. Chem. 2003, 278:50702-50713. 18. D. Ambrosi, A. Gamba, amd G. Serini. Cell directional persistence and chemotaxis in vascular morphogenesis. Bull. Math Biol. 2004 Nov;66(6):1851-1873. 19. G. Serini1 and F. Bussolino. Common cues in vascular and axon guidance. Physiology (Bethesda) 2004, 19:348-354. 1Corresponding Author. Review. 20. P. Conrotto, D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 2005, 105:4321-4329. 5 21. I. Cascone, L. Napione, F. Maniero, G. Serini, and F. Bussolino. Stable interaction between 51 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J. Cell Biol. 2005, 170:993-1004. 22. A. Gamba, A. de Candia, S. Di Talia, A. Coniglio, F. Bussolino, and G. Serini. Diffusion-limited phase separation in eukaryotic chemotaxis. Proc. Natl. Acad. Sci. USA 2005, 102:16927-16932. 23. G. Serini1, D. Valdembri, and F. Bussolino. Integrins and angiogenesis: a sticky business. Exp. Cell Res. 2006, 312:651-658. 1Corresponding Author. Review. 24. A. Vacca, C. Scavelli, G. Serini, G. Di Pietro, T. Cirulli, F. Merchionne, D. Ribatti, F. Bussolino, D. Guidolin, G. Piaggio, A. Bacigalupo, and F. Dammacco. Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 2006, 108:1661-1667. 25. S. Di Talia, A. Gamba, F. Lamberti, and G. Serini. Role of repulsive factors in vascularization dynamics. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 2006, 73:041917. 26. F. Bussolino, D. Valdembri, F. Caccavari, and G. Serini. Semaphoring vascular morphogenesis. Endothelium. 2006, 13:81-91. Review. 27. L. Zammataro, G. Serini, T. Rowland, and F. Bussolino. Embryonic cleavage modeling as a computational approach to sphere packing problem. J. Theor. Biol., 2006, 245:77-82. 28. A. de Candia, A. Gamba, F. Cavalli, A. Coniglio, S. Di Talia, F. Bussolino, and G. Serini. A simulation environment for directional sensing as a phase separation process. Science Signaling, 2007, 378:pl1. 29. F. Cavalli, A. Gamba, G. Naldi, M. Semplice, D. Valdembri and G. Serini. 3D simulations of early blood vessel formation. J. Comput. Physics, 2007, 225:2283-2300 30. L. Napione, I. Cascone, S. Mitola, G. Serini, and F. Bussolino. Integrins: a flexible platform for endothelial vascular tyrosine kinase receptors. Autoimmun. Rev. 2007 7:18-22. 31. G. Serini, L. Napione, and F. Bussolino. Integrins team up with tyrosine kinase receptors and plexins to control angiogenesis. Curr. Opin. Hematol., 2008, 78:213-222. Review. 32. G. Serini, L. Napione, M. Arese, and F. Bussolino. Beside adhesion: New perspectives of integrin functions in angiogenesis. Cardiovasc. Res., 2008, 15:235-242. Review. 33. F. Orso, E. Penna, D. Cimino, E. Astanina, F. Maione, D. Valdembri, E. Giraudo, G. Serini, P. Sismondi, M. De Bortoli, and D.Taverna. AP-2α and AP-2γ Regulate Epithelial Tumor Progression via Specific Genetic Programs. FASEB J., 2008, 22: 2702-2714. 34. A. Gualandris, A. Noghero, M. Geuna, M. Arese, D. Valdembri, G. Serini, F. Bussolino. Microenvironment drives the endothelial or neural fate of differentiating embryonic stem cells coexpressing neuropilin-1 and Flk-1. FASEB J. 2009 , 23:68-78. 35. D. Valdembri, P.T. Caswell, K.I. Anderson, J.P. Schwarz, I. König, E. Astanina, F. Caccavari, J.C. Norman, M.J. Humphries, F. Bussolino, G. Serini. Neuropilin−1/GIPC1 Signaling Regulates α5β1 Integrin Traffic and Function in Endothelial Cells. PLoS Biology 2009, 7:e1000025. doi:1000010.1001371/journal.pbio.1000025. 36 G. Serini1, F. Maione, E. Giraudo, F. Bussolino. Semaphorins and tumor angiogenesis. Angiogenesis 2009, 12:187-193. 1Corresponding Author. Review. 6 37. F. Maione, F. Molla, C. Meda, R. Latini, L. Zentilin, M. Giacca, G. Seano, G. Serini1, F. Bussolino1, E. Giraudo1. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J. Clin. Invest. 2009, 119: 3356-3372. 1 Shared senior authorship. 38. A. Veglio, A. Gamba, M. Nicodemi, F. Bussolino, G. Serini. A symmetry breaking mechanism for epithelial cell polarization. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 2009, 80:031919. 39. F. Bussolino, F. Caccavari, D. Valdembri, G. Serini. Angiogenesis: a balancing act between integrin activation and inhibition? Eur. Cytokine Netw. 2009, 20:191-196. Review. 40. F. Chianale, E. Rainero, P.E. Porporato, C. Cianflone, V. Bettio, N. Filigheddu, G. Baldanzi, G. Serini, F. Sinigaglia, A. Graziani. Diacylglycerol kinase α mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI. Proc. Natl. Acad. Sci. USA 2010, 107:4182-4187. 41. F. Caccavari, D.Valdembri, C. Sandri, F. Bussolino, G. Serini. Integrin signaling and lung cancer. Cell Adh. Migr. 2010, 4:1-6. Review. 42. M. Santambrogio, D. Valdembri, G. Serini. Increasing traffic on vascular routes. Mol. Aspects Med. 2011, 32:112-22. Review. 43. D. Valdembri, C. Sandri, M. Santambrogio, G. Serini. Regulation of integrins by conformation and traffic: it takes two to tango. Mol. Biosyst. 2011, 7:2539-2546. Review. 44. M. Arese, G. Serini, F. Bussolino. Nervous vascular parallels: axon guidance and beyond. Int. J. Dev. Biol. 2011, 55:439-445. Review. 45. K. Zylbersztejn, M. Petkovic, A. Burgo, M. Deck, S. Garel, S. Marcos, E. Bloch-Gallego, F. Nothias, G. Serini, D. Bagnard, T. Binz, T. Galli. The vesicular SNARE Synaptobrevin is required for Semaphorin 3A axonal repulsion. J. Cell Biol. 2012, 196:37-46. 46. G. Naldi, M. Semplice, A. Veglio, G. Serini, A. Gamba. A bistable model of cell polarity. PLoS one, 2012, 7:e30977. 47. F. Maione, S. Capano, D. Regano, L. Zentilin, M. Giacca, O. Casanovas, F. Bussolino, G. Serini, E. Giraudo. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J. Clin. Invest. 2012, 112: in press. doi:101172/JCI58976 Book chapters 1. F. Bussolino, M. Arese, E. Audero, E. Giraudo, S. Marchiò, S. Mitola, L. Primo, and G. Serini. Biological “Aspects of Tumor Angiogenesis”, in Cancer Modelling and Simulation (ed. L. Preziosi), pp. 1-22, Chapman & Hall/CRC, London, UK, 2003. 2. A. de Candia, A. Gamba, F. Cavalli, A. Coniglio, S. Di Talia, F. Bussolino, and G. Serini. “A computational model for eukaryotic directional sensing”. in Computational methods in systems biology, Proceedings (Lecture notes in computer science) Vol. 4210, pp. 184-195, Springer Verlag, Berlin, Germany, 2006. 3. G. Serini and F. Bussolino. “Role of integrins in angiogenesis”. in Angiogenesis: Basic Science and Clinical Applications, pp. 133-147, Editors: M.E. Maragoudakis and E. Papadimitriou, Transworld Research Network, Kerala, India, 2007. 7 4. G. Serini, S. Sigismund, and L. Lanzetti. "Endocytosis and exocytosis in signal transduction and in cell migration". In Membrane Trafficking, ISBN 978-953-307-776-5, InTech, Rijeka, Croatia, 2011. In press. 8