Marc Symons, PhD
Investigator, Center for Oncology and Cell Biology
Director, Light Microscopy Facility
350 Community Drive, Manhasset, NY 11030
E-mail: msymons@nshs.edu
Phone: (516) 562-1193
Fax: (516) 562-1022

Academic Degrees:
Licentiaat (equivalent to B.S.) in Physics, 1975, Universitaire Instelling Antwerpen, Belgium
Ph.D. in Biophysics, 1980, Vrije Universiteit Brussel, Belgium

Affiliations:
- Member, Cushing Brain Tumor Institute at North Shore-LIJ
- Associate Professor, Department of Anatomy & Structural Biology, Albert Einstein College of Medicine
- Member, Albert Einstein Cancer Center

Research Overview:

We investigate the infiltration of brain tumor cells into the normal brain. This process, termed invasion, strongly limits the effectiveness of both surgical intervention and radiation therapy. Moreover, invading brain tumor cells have increased resistance to chemo and radiation therapy. Although brain tumor invasiveness has been extensively studied for decades, there are still no anti-invasion therapies available. We are studying two highly invasive brain tumors, glioblastoma and medulloblastoma. Glioblastoma is one of the most aggressive of all human cancers, newly diagnosed patients typically have survival time of about one year.

Medulloblastoma is the most common malignant childhood brain tumor. The goal of the laboratory is to identify signaling proteins that are essential for the invasiveness of glioblastoma or medulloblastoma and that are aberrantly activated in these tumors. We are focusing our attention on signaling pathways that are controlled by members of the Rho family of small GTPases.

Research Description:

Research in the laboratory focuses on the diffusive infiltration of brain tumor cells deep into the normal brain. The spread of brain tumor cells strongly limits the effectiveness of both surgical intervention and radiation therapy. Invading brain tumor cells also have increased resistance to chemo and radiation therapy. Therefore, restraining brain tumor invasiveness, in addition to limiting tumor spread may also make these tumors more susceptible to therapeutic interventions.

We are studying two highly invasive brain tumors, glioblastoma and medulloblastoma. Glioblastoma is one of the most aggressive of all human cancers, with a medium survival time of about one year. Medulloblastoma is the most common malignant pediatric brain tumor and accounts for over 20% of all pediatric brain tumors. The goal of the laboratory is to identify signaling proteins that are essential for the invasiveness of glioblastoma or medulloblastoma and that are aberrantly activated in these tumors.

Roles of Rho GTPases and their guanine nucleotide exchange factors in brain tumors.

Over the past several years, we have identified two key signaling proteins, Rac1 and Cdc42, which play critical roles in the invasive behavior of both glioblastoma and medulloblastoma. Moreover, we have demonstrated that the Rac1 GTPase is hyperactive both in glioblastoma and medulloblastoma tumors. Elucidation of the signaling cascades that are controlled by Rac1 and Cdc42 therefore should yield novel targets for the discovery of anti-invasion drugs. Both Rac1 and Cdc42 are members of the Rho family of small GTPases. These GTPases coordinate a large number of cell biological functions, including cell migration and adhesion. The overarching goal of several projects in our laboratory is to elucidate the signaling pathways that are responsible for the activation of these GTPases in brain tumors. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs). We have identified 8 different Rho family GEFs that are essential for glioblastoma invasion. This work was performed in collaboration with the laboratories of Dr. Nhan Tran and Dr. Michael Berens at The Translational Genomics Research Institute, Phoenix, AZ and the laboratory of Dr. Jim Rutka, The Hospital for Sick Children at the University of Toronto, Canada. For some of these GEFs, including Ect2, Vav3 and Trio, we have been able to show that they are overexpressed in glioblastoma in comparison to non-neoplastic brain. We currently are extending these studies to characterize the spectrum of GEFs that is responsible for the invasive behavior of medulloblastoma.

Our efforts are now geared toward identifying the signaling mechanisms that are responsible for the activation of several of these GEFs. To further validate these novel potential therapeutic targets, we also are determining the activation state of these GEFs in brain tumor tissue obtained from patients through the Tissue Donation Program. We further plan to examine the role of these GEFs in the invasive behavior of both glioblastoma and medulloblastoma using animal models. In collaboration with the laboratory of Dr. Yousef Al-Abed at The Feinstein Institute for Medical Research and the laboratories of Dr. Nhan Tran and Dr. Nathalie Meurice at The Translational Genomics Research Institute, we have also established an effort to identify Rho GEF small molecule inhibitors. 

Synaptojanin 2, a critical regulator of invadopodia.

One signaling element that is controlled by Rac1 to drive tumor cell invasion is the phosphatidylinositol phosphatase synaptojanin 2. We have shown that synaptojanin 2 regulates the formation of invadopodia, actin-based structures at which extracellular matrix proteases are concentrated. Invadopodia are thought to be critical for the invasive behavior of malignant tumor cells. We have identified a large number of proteins that interact with synaptojanin 2. Some of these proteins are regulated by phosphatidylinositol lipids that are substrates or products of synaptojanin 2, whereas others are involved in the regulation of synaptojanin 2. The molecular mechanisms that underlie these signaling events are under investigation. Our resultes indicate that synaptojanin 2 functions as a scaffold that orchestrates essential signaling events in invadopodia.

Brain tumor stem cells

An emerging interest in the laboratory is the analysis of the behavior of brain tumor stem cells that are isolated from brain tumor specimens. Brain tumor stem cells appear to be critical for tumor development and are thought to be responsible for tumor resistance to radio- and chemo-therapy. Topics that are under investigation include how and to what extent brain tumor stem cells contribute to the invasive behavior of brain tumors and to characterize components of the brain tumor stem cell niche, the microenvironment of the brain tumor stem cells that nurtures and protects them.

Recurrent respiratory papillomatosis

Over the past several years, the laboratory developed a collaboration with the Steinberg laboratory at the Feinstein Institute, which is studying recurrent respiratory papillomatosis caused by human papillomavirus infection of mucosal tissues of the airway. Focus is on Rac1-regulated signal transduction mechanisms that lead to increased expression of COX-2.

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Lab Members:

Name:   Amanda Chan, PhD
Position:   Research Scientist
Research:   Studies the role of RhoG, another Rho family member in glioblastoma invasion. She is also in charge of the Light Microscopy Core Facility.
E-mail:   achan@nshs.edu

Name:   Sehba Dsilva, MD
Position:   Postdoctoral Research Fellow
Research:   Studies Shwachman-Diamond syndrome and Diamond Blackfan anemia.
E-mail:   sdsilva@nshs.edu

Name:   Yayu Chuang, MS
Position:   Research Associate
Research:   Investigates the functional properties of synaptojanin 2.
E-mail:   ychuang@nshs.edu

Name:   Yu-Ping Yang, MS
Position:   Research Assistant
Research:   Studies Rho family activators in medulloblastoma.
E-mail:   yyang1@nshs.edu

Name:  Sebastien Didier
Position: Research Assistant
Education: M.S. Cellular Biology and Proteomics, Univeristy of Lille I, Lille, France
E-mail:  dsebasti@nshs.edu

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Selected Publications:

Symons M and Segall JE. Rac and Rho driving tumor invasion: who’s at the wheel? 2009, Genome Biology 10:213. [Epub ahead of print]

Symons M. Watching the First Steps of Podosomes. 2008, Current Biol. 18, R925-R927.

Salhia B, Tran NL, Wolf A, Nakada M, McDonough WS, Chan A, Rutka F, Berens ME, Symons M and Rutka JT. The guanine nucleotide exchange factors Trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. 2008, Am. J. Pathology 173:1828-38.

Coniglio SJ, Zavarella S and Symons M. Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms. 2008, Mol. Cell. Biol. 28: 4162-72.

Chuang Y, Valster A and Symons M. The atypical Rho family GTPase Wrch-1 regulates focal adhesion formation and cell migration. 2007, J. Cell Sci. 120: 1927-34.
Wu R, Congilio SJ, Chan, A, Symons M and Steinberg B. Up-regulation of Rac1 by epidermal growth factor mediates Cox-2 expression in recurrent respiratory papillomas. 2007, Mol. Med. 13: 143-50.

Chan AY, Akhtar M, Zhen, Y, Brenner, M, Gulko, PS and Symons M. The small GTPase Rac regulates the proliferation and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. 2007, Mol. Med. 13: 297-304.

Salhia B, Tran NL, Symons M, Winkles JA, Rutka JT, Berens ME. Molecular Pathways Triggering Glioma Cell Invasion. 2006, Expert Rev. Mol.Diagn. 6, 613-26.

Tran NL, McDonough WS, Savitch BA, Nakada M, Fortin SP, Winkles JA, Symons M, Cunliffe HE, Hostetter G, Hoelzinger DB, Rennert JL, Michaelson JS, Burkly LC, Lipinski CA, Loftus JC, Mariani L and Berens ME. Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-B and correlate with poor patient outcome. 2006, Cancer Res, 66:9535-42.

Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR and Symons M. Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. 2005, Oncogene. 24, 7821-9.

Valster A, Tran NL, Nakada M, Berens ME, Chan AY and Symons M. Cell migration and invasion assays. 2005, Methods 37, 208-15.

Chuang Y, Tran NL, Rusk N, Nakada N, Berens ME and Symons M. Role of synaptojanin 2 in glioma cell migration and invasion. 2004, Cancer Res. 64, 8271-8275.
Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M, Segall J, Eddy R, Miki H, Takenawa T, and Condeelis J. Molecular mechanisms of invadopodium formation: the role of the N-WASP–Arp2/3 complex pathway and cofilin. 2005, J. Cell Biol. 168: 441-52.

Symons M, editor. “Rho GTPases”. 2004, Kluwer/Landes Bioscience, pp. 235.

Symons M and Rusk N. Control of vesicular trafficking by Rho GTPases. 2003, Current Biology 13, R409-18.

Rusk N, Le P,  Mariggio S, Guay G, Iurisci C, Nabi IR, Corda D and Symons M. Synaptojanin 2 functions at an early step of clathrin-mediated endocytosis. 2003, Current Biology 13, 659-63.

Banyard J and Symons M. Cell motility and invasion assays. 2002, Methods Mol. Biol. 189, 129-40.

Van Aelst L and Symons M. Role of Rho family GTPases in epithelial morphogenesis. 2002, Genes Dev. 16, 1032-54.
Giodini A, Kallio MJ, Wall NR, Gorbsky GJ, Tognin S, Marchisio PC, Symons M, and Altieri DC. Regulation of microtubule stability and mitotic progression by survivin. 2002, Cancer Res. 62, 2462-67.
Bouzahzah B, Albanese C, Ahmed F, Pixley F, Lisanti MP, Segall JD, Condeelis J, Joyce D, Minden A, Der CJ, Chan A, Symons M and Pestell RG. Rho family GTPases regulate mammary epithelium cell growth and metastasis through distinguishable pathways. 2002, Mol. Med. 7, 816-30.

Ruggieri R, Chuang YY and Symons M. The small GTPase Rac1 suppresses apoptosis caused by growth factor deprivation in fibroblasts. 2001, Mol. Med. 7, 293-300.

Coniglio SJ, Jou T-S, and Symons M. Rac1 protects epithelial cells against anoikis. 2001; J. Biol. Chem. 276: 28113-20.

Malecz N, McCabe PC, Spaargaren C, Qiu R-G, Chuang Y-Y, and Symons M. Synaptojanin 2, a novel Rac effector that inhibits clathrin-mediated endocytosis. 2000, Current Biology 10: 1383-1386.

Symons M and Settleman J. Rho family GTPases: More Than Simple Switches? 2000, Trends Cell Biol. 10, 415-9.
Crompton AM, Roscoe W, Foley LH, Wood A, Stokoe D, McCormick F, Symons M and Bollag G. Regulation of Tiam1 nucleotide exchange activity by pleckstrin domain binding ligands. 2000, J. Biol. Chem. 275, 25751-25759
Banyard J, Anand-Apte B, Symons M and Zetter BR. Differential modulation of     fibroblast invasion and migration by Rho family GTPases. 2000, Oncogene, 19, 580-91.

Symons M. Signaling pathways controlled by Rho family GTP-binding proteins. In:
“Signal Transduction, Cell Cycle and their inhibitors” (Gutkind S, editor). 2000, Humana Press, pp. 231-245.

Kheradmand F, Werner E, Tremble P, M. Symons and Werb Z. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. 1998, Science 280, 898-902.
Clark E, King W, Brugge J, Symons M and Hynes R. Integrin-mediated signals regulated by members of the Rho-family of GTPases. 1998, J. Cell Biol. 142, 573-586.

Anand-Apte B, Zetter BR, Viswanathan A, Qiu R-G, Ruggieri R, Chen J and Symons M. PDGF- and fibronectin-stimulated migration are differentially regulated by the Rac and ERK pathways. 1997. J. Biol Chem. 272, 30688-92.

Qiu R-G, Abo A, McCormick F and Symons M.  Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation. 1997, Mol. Cell. Biol. 17, 3449-58.

Westwick JK, Lambert QT, Clark GJ, Symons M, Van Aelst L, Pestell RG and Der CJ. Rac regulation of transformation, gene expression and actin organization by multiple, PAK-independent pathways. 1997, Mol. Cell. Biol. 17, 1324-35.
Hess JA, Ross AH, Qiu R-G, Symons M and Exton JJ. Role of Rho family proteins in phospholipase D activation by growth factors. 1997, J. Biol. Chem. 272, 1615-1620.

Symons M. Rho family GTPases: The cytoskeleton and beyond. 1996, TIBS 21, 178-81.

Symons M, Derry JMJ, Karlak B, Jiang S., McCormick F, Francke U and Abo A. Wiskott-Aldrich Syndrome Protein, a novel effector for the GTPase Cdc42Hs, is implicated in actin polymerization. 1996; Cell 84: 723-734.
Hawkins PT, Eguinoa A, Qiu R-G, Stokoe D, Cooke FT, Walters R, Jackson T, Wennström S, Claesson-Welsh L, Evans T, Symons M and Stephens L.  PDGF stimulates an increase in GTP-rac via the activation of phosphoinositide 3OH-kinase.  1995, Current Biology 5, 393-403.
Siddiqi AR, Smith JL, Ross AH, Qiu R-G, Symons M and .Exton JH. Regulation of Phospholipase D in HL60 Cells.  Evidence for a Cytosolic Phospholipase D.   1995, J. Biol. Chem. 270, 8466-8473.

Qiu R-G, Chen J, McCormick F and Symons M. A role for Rho in Ras transformation. 1995, PNAS 92, 11781-85.

Peppelenbosch MP, Qiu R-G, deVries-Smits AMM, Tertoolen LGJ, de Laat SW, Burgering BMT, McCormick F, Hall A, Symons M and Bos JL.  Rac mediates epidermal growth factor-induced rho-activation via arachidonic acid release.  1995, Cell 81, 849-56.

Qiu R-G, Chen J, Kirn D, McCormick F and Symons M. An essential role for Rac in Ras transformation. 1995; Nature 374: 457-459.

Freed E, Symons M, Macdonald SG, McCormick F and Ruggieri R.  Binding of 14-3-3 Proteins to the Protein Kinase Raf and Effects on Its Activation. 1994, Science 265, 1713-6.

Stokoe D, Macdonald SG, Cadwallader K, Symons M and Hancock JF.  Activation of Raf as a Result of Recruitment to the Plasma Membrane. 1994, Science 264. 1463-7.

Symons M and Mitchison T.  A GTPase controls cell-substrate adhesion in Xenopus XTC fibroblasts. 1992, J. Cell Biol. 118, 1235-44.

Symons M and Mitchison T.  Control of actin polymerization in live and permeabilized fibroblasts. 1991, J. Cell Biol. 114, 503-13.