Susan Meakin, PhD


Susan Meakin, Research Scientist, Professor of Biochemistry and Neuroscience

Why I Became a Scientist

To contribute to the advancement of medical research and the pursuit of knowledge. 

I believe in 2 adages: "Use it or lose it" as well as one quoted by the English philosopher, Sir Francis Bacon (1561-1626), "Knowledge is power".

I believe that by continuing to improve our understanding of how biology works that we will become empowered to utilize this knowledge to the fullest potential and to develop better diagnostic and/or therapeutic approaches to aid medical health care in Canada and abroad.  

My primary areas of interest are cancer biology as well as neuronal development, in particular, understanding the molecular basis of cortical development in the brain, the stability of axonal projections and transport of molecular cargo essential as well as the molecular basis of learning and memory.

Research Summary

My research centers around the signalling properties of a family of cell surface receptors, termed Trks, which are expressed exclusively in the developing and mature nervous systems.  Trk receptors regulate the development of multiple types of neurons in the brain as well as the process of learning and memory. 

Specifically, I have focussed on identifying novel intracellular molecules (FRS3, Nesca, RasGrf1)  that interact with the Trk receptors and in characterizing how they are involved in facilitating neuronal development and brain function as well as how they facilitate the ability of Trk receptors to communicate (cross-talk) with excitatory neurotransmitter receptors which control the process of learning and memory. 

My cancer biology interests involve characterizing a novel signaling mechanism, termed macropinocytosis, used by the Trk receptors to kill two different types of brain tumours, namely, medulloblastomas in children and glioblastomas in adults, by a novel mechanism involving cross-talk with GPCR coupled receptors.  Importantly, this process can be used to kill tumors that are resistant to other forms of cell death such as apoptosis.

All of the research in my lab utilizes a variety of molecular, genetic and cell biology approaches including primary cell culture, confocal microscopy and animal models.   Where appropriate, we also seek collaborations with local and international colleagues.

Research Questions and Disease Implications

How does Trk receptor activation kill brain tumours?

We are characterizing how Trk is cross-talking to a specific class of GPCRs and identifying the key enzymes involved in the activation of macropinocytosis-dependent cell death in brain tumors.  We will determine whether the GPCR status of particular tumors can be used as a biomarker to predict which tumors will be sensitive to this form of cell death and will investigate how to activate these enzymes through the use of drugs and/or mimetics.  We are also collaborating with Dr. Bartha at the Robarts Research Institute in developing novel contrast agents that will enhance the identification of brain tumors in live animal imaging studies.

Medulloblastomas (kids 2-10) --> tumours of the developing cerebellum.  They respond poorly to conventional chemotherapy approaches.
Glioblastomas (Adults) --> tumours generated from astrocytes in the brain.  These are very aggressive and lethal tumours.

How does FRS3 function as a novel Autism Associated Gene?

We identified the signaling adapter termed Fibroblast Growth Factor (FGF) Receptor Substrate 3 (FRS3) as a novel adapter of both Trk receptors as well as FGF receptors.  The FGFs are a large family of growth factors that serve several roles in both neuron and brain development as well as in the mature brain.  We are investigating how FRS3 impacts brain development as well as animal behavior with the use of a mouse model in which FRS3 is not expressed in the developing cortex.  Importantly, we find that mice lacking one copy of the FRS3 gene have developmental brain defects as well as show agressive, hyperactive behaviors.  Since FRS3 has been identified as an Autism Associated Gene, we are characterizing the multiple roles that FRS3 serves in neurons including neurite outgrowth and stability as well as the molecular transport of exitatory neurotransmitters.

How do Trk receptors facilitate learning and memory?

The ligand for the TrkB receptor, termed brain-derived neurotrophic factor (BDNF), has been shown to facilitate the process of learning and memory.  However, the TrkB receptor does not directly regulate neuronal activity that is required to facilitate this process.  We have been characterizing the signaling mechanism of how TrkB facilitates learning and memory development and have identified a receptor cross-talk mechanism that involves exitatory glutamate receptors termed NMDA receptors as well as the signaling molecule termed RasGrf1.  Better understanding of this mechanism will guide future studies directed at improving learning disorders.

Education

B.Sc., Honors Microbiology, U. of Guelph (1983)
Ph.D., Medical Genetics and Medical Biophysics, U. of Toronto (1987)

Training

Post Doctoral Fellow, Dept. of Neurobiology, Stanford University (1988-1991)

Awards

•  1982  NSERC Summer Research Award, Connaught Laboratories
•  1984  Research Training Appointment, Hospital for Sick Children
•  1985  First Prize, Graduate Student Paper Competition
   Annual Meeting, The Genetics Society of Canada
•  1984 - 1987 Ontario Graduate Scholarships
   Department of Medical Genetics and Medical Biophysics
   University of Toronto
•  1988 - 1991 Postdoctoral Research Fellowship
   Medical Research Council of Canada (declined)
• 1988 - 1991 Fellow, Cancer Research Fund of the Damon Runyon - Walter Winchell Foundation, DRG-984
• 1994 - 1999 Medical Research Council of Canada, Scholarship Award
• 1994 - 2000 National Cancer Institute of Canada, Research Scientist Career Award   (declined)
• 1999 - 2001 The EJLB Foundation, Scholarship Research Program
• 2000 - 2005 Premier’s Research Excellence Award

Publications

• Li, C., J.I.S. MacDonald, A. Talebian, J. Leunenberger, C. Seah, S.H. Pasternak, S.W. Michnick and S.O. Meakin. 2015. Trk-induced macropinocytosis in medulloblastoma Daoy cells requires the FRS2-dependent activation of Src, H-Ras, RhoA and the CK1-dependent inactivation of RhoB. Nature Cell Biology (in preparation).

• McVicar, N., A.X. Li, S.O. Meakin and R. Bartha. 2015. Imaging chemical exchange saturation transfer (CEST) effects following tumor-selective acidification using lonidamine. NMR in Biomed. DOI: 10.1002/nbm.3287

Zhou, L., A. Talebian and S.O. Meakin. 2015. The signaling adapter, FRS2, facilitates neuronal branching in primary cortical neurons via both Grb2 and Shp2 dependent mechanisms. J. Mol. Neurosci55(3):663-677.

• McVicar, N., A. Li, D. Gonçalves, M. Bellyou, S. Meakin, M. Prado and R. Bartha.  2014. Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI. J. Cereb. Blood Flow Metab. 34(4): 690-698.

• Thangiah, G, S.D. Rege, S.E. Mathews, S.O. Meakin, M.W. White and J.R. Babu.  2013. Nerve growth factor receptor TrkA, a new receptor in insulin signaling pathway in PC12 cells. J. Biol. Chem. 288(13): 23807-23813.

• Talebian, A., K.N. Robinson and S.O. Meakin. 2013. Ras guanine nucleotide releasing factor 1 (RasGrf1) enhancement of Trk Receptor mediated neurite outgrowth requires activation of both H-Ras and Rac. J. Mol. Neurosci. 49(1): 38-51.

• MacDonald, J.I.S., A. Dietrich, S. Gamble, T. Hryciw, R.I. Grant and S.O. Meakin. 2012.  Nesca, a novel neuronal adapter protein, links the molecular motor kinesin with the pre-synaptic membrane protiein, syntaxin-1, in hippocampal neurons. J. Neurochem. 121(6): 861-880.

• Valencia, T., A Joseph, N. Kachroo, S Darby, S.O. Meakin and VJ Gnanapragasam. 2011. Role and expression of FRS2 and FRS3 in prostate cancer. BMC Cancer 11:484.

• Li, A., M. Suchy, C. Li, J.S. Gati, S. Meakin, R. H.E. Hudson, R.S. Menon and R. Bartha. 2011. In vivo detection of MRI-PARACEST agents in mouse brain tumors at 9.4 Tesla. Magn. Reson. Med. 66(1) 67-72.

• Hryciw, T., J.I.S. MacDonald, R. Phillips, C. Seah, S. Pasternak and S.O. Meakin. 2010.  The fibroblast growth factor receptor substrate 3 (Frs3) is a developmentally regulated microtubule-associated protein expressed in migrating and differentiated neurons.  J. Neurochem. 112(4): 924-939.

• Li, C., J.I.S. MacDonald, T. Hryciw and S.O. Meakin. 2010. Nerve growth factor activation of the TrkA receptor induces cell death, by macropinocytosis, in medulloblastoma Daoy cells.  J. Neurochem. 112(4): 882-899

• Dixon*, S., J.I.S. MacDonald*, K. N. Robinson, C.J. Kubu and S.O. Meakin. 2006. Trk receptor binding and neurotrophin/fibroblast growth factor (FGF)-dependent activation of the FGF receptor substrate (FRS)-3. BBA. Biochim. Biophysics. Acta 1763(4): 366-380, * co-first authors

• Robinson, K.N., K. Manto, R.J. Buchsbaum, J. I. S. MacDonald and S.O. Meakin.  2005. Neurotrophin-dependent tyrosine phosphorylation of Ras guanine-releasing factor 1 and associated neurite outgrowth is dependent on the HIKE domain of TrkA. J. Biol. Chem. 280(1): 225-235.

• MacDonald, J.I.S., C. J. Kubu and S.O. Meakin. 2004.  Nesca, a novel adapter, translocates to the nuclear envelope and regulates neurotrophin-induced neurite outgrowth. J. Cell Biol. 164(6): 851-862.

Contact Information

Susan O. Meakin, PhD.
Scientist, Molecular Medicine: Vascular and Brain Health Group
The Robarts Research Institute
1151 Richmond St. N.
London, On, N6A 5B7
smeakin@robarts.ca

 

Tel: 519-931-2777 x24304
Fax: 519- 931-5222

Administrative Assistant:
Maria Sinacori
Tel: (519) 931-5777 ext. 24118
msinacori@robarts.ca