Neuroscience Research Program
BA (English Literature), University of Michigan; MA (Philosophy), Harvard University; MD, Northwestern University; PhD (Neurobiology), National Institute of Neurological Disorders and Stroke, National Institutes of Health
Associate Scientist in the Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michaels Hospital
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for SickKids
Division of Neurosurgery, Department of Surgery, University of Toronto
Glioblastoma, Neural Stem Cells, Epigenetics, Microenvironment, Awake Craniotomy
Phone: 416 864 5548
Das, S., Srikanth, M., & Kessler, J. A. (2008). Cancer stem cells and glioma.Nature Clinical Practice Neurology, 4(8), 427-435.
Yadav, A. K., Renfrow, J. J., Scholtens, D. M., Xie, H., Duran, G. E., Bredel, C., Vogel, H., Chandler, J. P., Chakravarti, A., Robe, P. A., Das, S., Scheck, A. C., Kessler, J. A., Soares, M. B., Sikic, B. I., Harsh, G. R., & Bredel, M. (2009). Monosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas. JAMA: the journal of the American Medical Association, 302(3), 276-289.
Gobeske, K. T., Das, S., Bonaguidi, M. A., Weiss, C., Radulovic, J., Disterhoft, J. F., & Kessler, J. A. (2009). BMP signaling mediates effects of exercise on hippocampal neurogenesis and cognition in mice. PLoS One, 4(10), e7506.
Srikanth, M., Das, S., Berns, E. J., Kim, J., Stupp, S. I., & Kessler, J. A. (2013). Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition. Neuro-oncology,15(3), 319-329.
Growth factor signaling drives glioma stem cell phenotype in glioblastoma. Given their import in normal stem cell microenvironments, we have examined the role of cell-extrinsic signaling in glioma stem cell (GSC) biology and resistance. We have focused on two signaling pathways known to be relevant to neural and glioma stem cells, TGF-β and BMP. Our work has identified regional and intercellular differences in glioma stem cell phenotype driven by extrinsic TGF-β and BMP signals. We have found that activation of the TGF-β pathway gives rise to a glioma stem cell that is highly proliferative and motile, but also sensitive to radiation- and chemotherapy-induced cell death. Conversely, BMP-positive glioma cells are relatively quiescent and stationary, but are resistant to radiation and chemotherapy. These findings correlate with the mesenchymal and proneural glioblastoma subtypes, in which TGF-β and BMP signaling predominate, respectively. Our studies show that cell-extrinsic signaling has profound effects on glioma stem cell phenotype and on outcomes in patients with glioblastoma. Our studies have been assembled into a manuscript that we are preparing for submission. We are currently examining micro-RNA networks that integrate TGF-β and BMP signaling at a subcellular level.
Angiocrine factors modulate stem-ness in neural and glioma stem cells. Neural and glioma stem cells are thought to reside within a stem cell niche, within which endothelial cells are important members. While endothelial cell signaling (angiocrine factors) is known to be relevant to neural stem cell (NSC) behavior, the particularities of that communication are less clear. We have focused on the role of the prostanoid family in NSC and GSC biology. Specifically, we have found that activation of prostaglandin E2 signaling results in enrichment of stem-like cells in NSC and GSC adherent cultures. Treatment of NSCs and GSCs with the prostaglandin analog, iloprost, results in increased expression of Sox2, while inhibition of prostaglandin with indomethacin results in decreased Sox2 expression. In addition, iloprost treatment results in GSC proliferation, while treatment with indomethacin suppresses proliferation in GSCs. We are now examining the effect of prostaglandin signaling on tumorigenicity in GSCs. Our next steps will involve explicating the role of prostaglandin signaling in glioma biology using both in vitro and in vivo studies.
None at this time