Giorgio Scita
e-mail: giorgio.scita AT ifom.eu
affiliation: IFOM-IEO Campus-Universita' di Milano
research area(s): Cell Biology, Cancer Biology
Course:
Molecular Medicine: Molecular Oncology and Computational Biology
University/Istitution: Università di Milano, UNIMI-SEMM
University/Istitution: Università di Milano, UNIMI-SEMM
E D U C A T I O N:
1986. University of Parma, Parma, Italy. Institute of Microbial genetic. Laurea (M.S. equivalent) in Biological Sciences.
1990. University of Parma, Parma, Italy. Institute of Biochemistry. Ph.D. in Food Chemistry and Technology.
PROFESSIONAL EXPERIENCE.
2006-present University of Milan, School of Medicine:
Associate Professor of Pathology.
2001-present: IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.
Unit Director. Molecular Mechanisms of signaling regulating membrane and actin dynamics.
1995-2001: European Institute of Oncology, Milan, Italy
Research Assistant: Molecular mechanisms of signal integration among GTPases.
1994-1995(Aug.): National Institute of Health, Bethesda, Maryland.
National Cancer Institute, Division of Cancer Etiology. Laboratory of Carcinogenesis and Tumor Promotion, Differentiation Control section.
Senior Post-doctoral fellow. Interplay between signaling mediated by Retinoic acid Receptors and the Ras oncogene.
1990-1994: University of California, Berkeley. Department of Nutritional Sciences.
Post-doctoral fellow. Metabolism of Vitamin A and effect of Retinoic Acid on cell adhesion.
1987-1990: University of Parma. Parma, Italy. Institute of Biochemistry. Graduate Student.
1986. University of Parma, Parma, Italy. Institute of Microbial genetic. Laurea (M.S. equivalent) in Biological Sciences.
1990. University of Parma, Parma, Italy. Institute of Biochemistry. Ph.D. in Food Chemistry and Technology.
PROFESSIONAL EXPERIENCE.
2006-present University of Milan, School of Medicine:
Associate Professor of Pathology.
2001-present: IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.
Unit Director. Molecular Mechanisms of signaling regulating membrane and actin dynamics.
1995-2001: European Institute of Oncology, Milan, Italy
Research Assistant: Molecular mechanisms of signal integration among GTPases.
1994-1995(Aug.): National Institute of Health, Bethesda, Maryland.
National Cancer Institute, Division of Cancer Etiology. Laboratory of Carcinogenesis and Tumor Promotion, Differentiation Control section.
Senior Post-doctoral fellow. Interplay between signaling mediated by Retinoic acid Receptors and the Ras oncogene.
1990-1994: University of California, Berkeley. Department of Nutritional Sciences.
Post-doctoral fellow. Metabolism of Vitamin A and effect of Retinoic Acid on cell adhesion.
1987-1990: University of Parma. Parma, Italy. Institute of Biochemistry. Graduate Student.
Tumor cells utilize highly versatile strategies and processes to invade into surrounding tissue. Cell migration, a hallmark of metastasis, is a typical case in point. Recent studies using in vitro surrogate assays to model 3D cell migration and in vivo analysis of invading tumors by multi-photon-microscopy[1], have revealed how tumor cells use different motility modes to disseminate. Each of these modes is driven and controlled by distinct molecular pathways [2,3]. The plasticity and versatility of tumor cell migration is a result of cells being able to switch between these migratory modes [4]. These adaptive responses provide migratory ‘escape’ strategies after pharmacotherapeutic intervention, by prompting alternative mechanisms of cancer cell dissemination in tissues that overcome single-pathway-hitting pharmacological weapons [4,5]. It is therefore essential to identify the various critical pathways and cellular processes that enable tumor cells to plastically adapt their motility modes during migration and invasion of surrounding tissues. Only after this knowledge has been gleaned, can pharmacological strategies targeted against multiple, deregulated tumor-specific migratory mechanisms, be devised and clinically tested with any hope of success.
An emerging critical process that regulates cell migratory modes is trafficking of plasma membrane components, such as Receptor Tyrosine Kinases (RTK) and integrins, and signaling molecules controlling actin dynamics-based motility and the localized production of intracellular-confined signaling cues [6]. However, little is known as to how membrane trafficking and actin-based, motility machineries are co-opted in invasive cancer cells, and which are the endocytic players and genetic programs implicated in regulation of tumor migratory modes and invasion. Similarly, the pathways controlling directional migration are incompletely defined.
The goal of our laboratory is, therefore, to identify and elucidate how endocytic/recyling and signaling components control the dynamic location of critical regulators of actin reorganization, and control the expression of genes needed for the correct execution and mantainance of migration programs and the acquisition of metastatic properties, particularly in response to stimulation of RTKs.
An emerging critical process that regulates cell migratory modes is trafficking of plasma membrane components, such as Receptor Tyrosine Kinases (RTK) and integrins, and signaling molecules controlling actin dynamics-based motility and the localized production of intracellular-confined signaling cues [6]. However, little is known as to how membrane trafficking and actin-based, motility machineries are co-opted in invasive cancer cells, and which are the endocytic players and genetic programs implicated in regulation of tumor migratory modes and invasion. Similarly, the pathways controlling directional migration are incompletely defined.
The goal of our laboratory is, therefore, to identify and elucidate how endocytic/recyling and signaling components control the dynamic location of critical regulators of actin reorganization, and control the expression of genes needed for the correct execution and mantainance of migration programs and the acquisition of metastatic properties, particularly in response to stimulation of RTKs.
Selected Publications
10 Toparticoli as Senior/Correpsonding Author
(Average Impact Factor = 16.45)
• 1) M. Hertzog, F. Milanesi, L. Hazelwood, A. Disanza, H. Liu, E. Perlade, M. Malabarba, S. Pasqualato, A. Maiolica, S. Confalonieri, C. Le Clainche, N. Offenhauser, J. Block, K. Rottner, P. P. Di Fiore, M.-F. Carlier, N. Wolkmann, D. Hanein, G. Scita, 2010. Molecular basis for the dual function of Eps8 on actin dynamics: bundling and capping. Plos Biology. June 8, e1000387.IF= 12.683 Citation=0
• 2) E. Menna, A. Disanza, C. Cagnoli, U. Schenk, G. Gelsomino, E. Frittoli, M. Hertzog, N. Offenhauser, C. Sawallisch, H. J. Kreienkamp, F. B. Gertler, P. P. Di Fiore, G. Scita, M. Matteoli, 2009. Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PLoS Biol. 7, e1000138. * Corresponding author. IF=12.683 Citation=9
• 3) Palamidessi, A, Frittoli, E. Faretta, M. Diaspro , A, Letizia Lanzetti, Scita, G.*and Di Fiore, P.P. Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell (2008). Jul 11;134(1):18-20. * Corresponding author IF=31.253 Citation=112
New & Views commentary for this article
-T. Zech and L. Machesky -Cell. 2008 Jul 11;134(1):18-20
- C. Marshall-Faculty 1000 Evaluated on 23 Jul 2008
-K. Baumann Nature Reviews Cancer 8, 662-663 (September 2008)
• 4) Disanza A, Mantoani S, Hertzog M, Gerboth S, Frittoli E, Steffen A, Berhoerster K, Kreienkamp HJ, Milanesi F, Di Fiore PP, Ciliberto A, Stradal TE, Scita G. 2006. Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex.
Nat Cell Biol 8:1337-1347. IF=17.774 Citation=54
• 5) Innocenti M, Gerboth S, Rottner K, Lai FP, Hertzog M, Stradal TE, Frittoli E, Didry D, Polo S, Disanza A, Benesch S, Di Fiore PP, Carlier MF, Scita G.. (2005). Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes.
Nat Cell Biol 7, 969-976 (2005). IF=17.774 Citation=84
• 6) Andrea Disanza, Marie-France Carlier , Theresia E. B. Stradal Dominique Didry , Emanuela Frittoli,, Stefano Confalonieri, Assunta Croce, Jurgen Wehland, Pier Paolo Di Fiore, and Giorgio Scita. Eps8 controls actin-based motility by capping the barbed ends of actin filaments.
Nat Cell Biol 6, 1180-8 (2004). IF=17.774 Citation=67
New & Views commentary for this article
-H.N. Higgs Nature Cell Biology 6, 1147 - 1149 (2004)
-Nature Cell Biology Cover (Nat Cell Biol 6, 1180-8 (2004))
• 7) Sini, P.Cannas, A.Koleske, A. J.Di Fiore, P. P., Scita, G. Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation.
Nat Cell Biol 6 (3), 268-274. (2004). IF=17.774 Citation=87
• 8) Metello Innocenti, Adriana Zucconi, Andrea Disanza, Emanuela Frittoli, Liliana Areces , Anika Steffen, Theresia E. B. Stradal, Pier Paolo Di Fiore, Marie-France Carlier, and G. Scita... Abi1 is essential for the formation and activation of a WAVE2 signalling complex.
Nat Cell Biol 6 (4), 319-327. (2004) IF=17.774 Citation=189
• 9) M. Innocenti, E. Frittoli, I. Ponzanelli, J.R. Falck, S.M. Brachmann, P.P. Di Fiore, and G. Scita. 2003. Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1.
J Cell Biol. 160 (1): 17-23. IF=9.52 Citation=115
• 10) Innocenti, M., P. Tenca, E. Frittoli, M. Faretta, A. Tocchetti, P.P. Di Fiore, and G. Scita. 2002. Mechanisms through which Sos-1 coordinates the activation of Ras and Rac.
J Cell Biol. 156:125-136. IF=9.52 Citation=93
5 Top Articles “reviews”
(Average Impact factor: 15.81)
• G. Scita and PP Di Fiore. The Endocytic Matrix.
Nature. Jan 28, 2010. IF=31.434 Citation=0
• 2) Scita, G., Confalonieri, S., Lappalainen, P. & Suetsugu, S. IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions.
Trends Cell Biol 18, 52-60 (2008). IF=13.385 Citation=29
• 3) Stradal, T.E. & Scita, G. Protein complexes regulating Arp2/3-mediated actin assembly.
Curr Opin Cell Biol (2005). Feb;18(1):4-10. 2006. IF=12.543 Citation=1
• 4)Theresia Stradal , Klemens Rottner , Andrea Disanza, Stefano Confalonieri, Metello Innocenti and Giorgio Scita.Regulation of actin dynamics by WASP and WAVE family proteins. 2004.
Trends in Cell Biology. Jun;14(6):303-11. IF=13.385 Citation=132
• 5) Scita, G., Tenca, P., Frittoli, E., Tocchetti, A., Innocenti, M., Giardina, G., and Di Fiore, P. P. (2000). Signaling from Ras to Rac and beyond: not just a matter of GEFs.
Embo J 19, 2393-8. IF=8.295 Citation=159
10 Toparticoli as Senior/Correpsonding Author
(Average Impact Factor = 16.45)
• 1) M. Hertzog, F. Milanesi, L. Hazelwood, A. Disanza, H. Liu, E. Perlade, M. Malabarba, S. Pasqualato, A. Maiolica, S. Confalonieri, C. Le Clainche, N. Offenhauser, J. Block, K. Rottner, P. P. Di Fiore, M.-F. Carlier, N. Wolkmann, D. Hanein, G. Scita, 2010. Molecular basis for the dual function of Eps8 on actin dynamics: bundling and capping. Plos Biology. June 8, e1000387.IF= 12.683 Citation=0
• 2) E. Menna, A. Disanza, C. Cagnoli, U. Schenk, G. Gelsomino, E. Frittoli, M. Hertzog, N. Offenhauser, C. Sawallisch, H. J. Kreienkamp, F. B. Gertler, P. P. Di Fiore, G. Scita, M. Matteoli, 2009. Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PLoS Biol. 7, e1000138. * Corresponding author. IF=12.683 Citation=9
• 3) Palamidessi, A, Frittoli, E. Faretta, M. Diaspro , A, Letizia Lanzetti, Scita, G.*and Di Fiore, P.P. Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell (2008). Jul 11;134(1):18-20. * Corresponding author IF=31.253 Citation=112
New & Views commentary for this article
-T. Zech and L. Machesky -Cell. 2008 Jul 11;134(1):18-20
- C. Marshall-Faculty 1000 Evaluated on 23 Jul 2008
-K. Baumann Nature Reviews Cancer 8, 662-663 (September 2008)
• 4) Disanza A, Mantoani S, Hertzog M, Gerboth S, Frittoli E, Steffen A, Berhoerster K, Kreienkamp HJ, Milanesi F, Di Fiore PP, Ciliberto A, Stradal TE, Scita G. 2006. Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex.
Nat Cell Biol 8:1337-1347. IF=17.774 Citation=54
• 5) Innocenti M, Gerboth S, Rottner K, Lai FP, Hertzog M, Stradal TE, Frittoli E, Didry D, Polo S, Disanza A, Benesch S, Di Fiore PP, Carlier MF, Scita G.. (2005). Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes.
Nat Cell Biol 7, 969-976 (2005). IF=17.774 Citation=84
• 6) Andrea Disanza, Marie-France Carlier , Theresia E. B. Stradal Dominique Didry , Emanuela Frittoli,, Stefano Confalonieri, Assunta Croce, Jurgen Wehland, Pier Paolo Di Fiore, and Giorgio Scita. Eps8 controls actin-based motility by capping the barbed ends of actin filaments.
Nat Cell Biol 6, 1180-8 (2004). IF=17.774 Citation=67
New & Views commentary for this article
-H.N. Higgs Nature Cell Biology 6, 1147 - 1149 (2004)
-Nature Cell Biology Cover (Nat Cell Biol 6, 1180-8 (2004))
• 7) Sini, P.Cannas, A.Koleske, A. J.Di Fiore, P. P., Scita, G. Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation.
Nat Cell Biol 6 (3), 268-274. (2004). IF=17.774 Citation=87
• 8) Metello Innocenti, Adriana Zucconi, Andrea Disanza, Emanuela Frittoli, Liliana Areces , Anika Steffen, Theresia E. B. Stradal, Pier Paolo Di Fiore, Marie-France Carlier, and G. Scita... Abi1 is essential for the formation and activation of a WAVE2 signalling complex.
Nat Cell Biol 6 (4), 319-327. (2004) IF=17.774 Citation=189
• 9) M. Innocenti, E. Frittoli, I. Ponzanelli, J.R. Falck, S.M. Brachmann, P.P. Di Fiore, and G. Scita. 2003. Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1.
J Cell Biol. 160 (1): 17-23. IF=9.52 Citation=115
• 10) Innocenti, M., P. Tenca, E. Frittoli, M. Faretta, A. Tocchetti, P.P. Di Fiore, and G. Scita. 2002. Mechanisms through which Sos-1 coordinates the activation of Ras and Rac.
J Cell Biol. 156:125-136. IF=9.52 Citation=93
5 Top Articles “reviews”
(Average Impact factor: 15.81)
• G. Scita and PP Di Fiore. The Endocytic Matrix.
Nature. Jan 28, 2010. IF=31.434 Citation=0
• 2) Scita, G., Confalonieri, S., Lappalainen, P. & Suetsugu, S. IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions.
Trends Cell Biol 18, 52-60 (2008). IF=13.385 Citation=29
• 3) Stradal, T.E. & Scita, G. Protein complexes regulating Arp2/3-mediated actin assembly.
Curr Opin Cell Biol (2005). Feb;18(1):4-10. 2006. IF=12.543 Citation=1
• 4)Theresia Stradal , Klemens Rottner , Andrea Disanza, Stefano Confalonieri, Metello Innocenti and Giorgio Scita.Regulation of actin dynamics by WASP and WAVE family proteins. 2004.
Trends in Cell Biology. Jun;14(6):303-11. IF=13.385 Citation=132
• 5) Scita, G., Tenca, P., Frittoli, E., Tocchetti, A., Innocenti, M., Giardina, G., and Di Fiore, P. P. (2000). Signaling from Ras to Rac and beyond: not just a matter of GEFs.
Embo J 19, 2393-8. IF=8.295 Citation=159
Project Title:
Project Title:
1) Molecular characterization of the network of proteins linking actin and membrane dynamics.
One still elusive aspect of the regulation of migratory and invasive protrusion is the mechanism that enables the force generating system of the actin polymerization machinery to be connected to the plasma membrane during the extension of polarized migratory protrusions. Within this context, we have characterized in vitro and in vivo the role of Eps8 as actin capping and bundling protein. One major interactor of Eps8 is the I-BAR-containing, membrane deforming protein IRSp53 (Disanza et al., 2006; Hertzog et al.; Menna et al., 2009), which represent an important effector linking Cdc42-pathways to membrane shape and dynamics with actin regulatory proteins, including, in addition to Eps8, also VASP family proteins. The mechanisms of action and functional role of Eps8 and IRSp53-based complexes remains largely to be established. To address these issues we plan to: 1) use in vitro reconstitution experiments of IRSp53-based complexes in conjunction with liposome and actin polymerization based assays; 2) characterize the phenotype of IRSp53 null mice and exploit cells derived from null mice to address the role of this protein in cell protrusions; 3) the knowledge of the mechanisms of regulation of this network will be further utilized to explore the mechanisms whereby elevated expression of Eps8 confers migratory and invasive advantages to a subset of tumor cells of oral squamous cell carcinoma, colon and pancreatic carcinoma.
Project Title:
2) Endocytic networks in the control of the plasticity of tumor cell migration
A number of our published (Palamidessi et al., 2008; Palamidessi et al., 2009) and unpublished data support the hypothesis that endocytic control of actin machinery is critical for the spatial restriction of signaling, and that it plays a key function in the regulation of migratory and invasive protrusions and in the plasticity of tumor cell motility through molecules and pathways that remain largely to be identified. The general goal of this proposal is, therefore, to identify critical components of the Endocytic Matrix that, by controlling the intracellular dynamic location of key regulators of actin reorganization, promote the formation of invasive cellular protrusions, the execution of migratory programs and, ultimately, the acquisition of metastatic properties. The strategy to achieve this goal combines medium-throughput RNAi-based High-content imaging screenings with a stepwise validation methodology based on in vitro culture model systems of tumor cell invasion and mouse model of metastasis.