Sunit Das

Dr. Das studied literature and philosophy at the University of Michigan and Harvard University before graduating from Northwestern University Medical School in Chicago, Illinois, in 2001.

He then pursued a PhD at the National Institutes of Health in Bethesda, Maryland, during which time he studied the biology of neural stem cells.

He entered the neurosurgical training program at Northwestern University in 2003. In 2010, he joined the faculty in the Division of Neurosurgery at St. Michael's Hospital and the University of Toronto.

His clinical interest is in the surgical management of malignant brain tumours and tumours involving the skull base.

His laboratory investigates the biology of stem cells in the normal brain and in primary brain tumours.

Research Synopsis

Our lab is interested in epigenetic regulation of cell identity in normal neural stem cells and glioblastoma.

Project #1.  We are interested in the role of long non-coding RNAs (lincs) in the control of cell fate in physiology and disease. In collaboration with Dr Phil Marsden, we have identified a novel linc, LIVE1, that mediates vascular maturation during normal blood vessel formation and coordinates angiogenesis in glioblastoma. Our current studies have focused on clarifying the mechanism by which LIVE1 acts, and in determining the role of linc-mediated angiogenesis in glioma biology.  Interestingly, we have found that LIVE1 is also highly expressed in metastatic but not primary melanoma and breast cancer. These findings, while preliminary, are very exciting and will instigate work in our lab to determine if LIVE1 has a role in metastatic progression in melanoma and breast cancer.

We have also begun work to identify lincs that are associated with the stem cell phenotype in NSCs and in glioblastoma.

Project #2. In a collaborative effort with Dr Warren Chan (Department of Chemistry, University of Toronto, http://inbs.med.utoronto.ca), we are working to develop nanobead-based imaging of glioma progression using CLARITY. We have developed a mouse model that will allow us to employ CLARITY to study glioma progression in the intact brain. This approach will elucidate our limited understanding of glioma cell invasion in the undisturbed state, and will serve as a model for future study of the mechanisms that underlie glioma progression. We will work closely with Dr Chan’s lab to develop nanobeads that can target glioma cells in the tumour and brain microenvironments.

Project #3. We have identified a quiescent CSC population in glioblastoma that is resistant to chemotherapy and responsible for tumour recurrence following treatment. Cell cycle entry in these cells is regulated though a double negative feedback loop involving ZEB1 and the mir-200 family, which are activated by TGF-β and BMP signaling, respectively.  We are working to delineate the mechanisms that control cell signaling in the glioma microenvironment and make sense of the effect of genomic signature on glioma behavior in this context.

Project #4. We performed a systematic review of the results of high-throughput screens from multiple CSC and physiologic stem cell systems to identify possible mediators of the stem cell phenotype in glioblastoma. Based on these results, we chose to study indomethacin, a chemical inhibitor of cyclooxygenase-2, and antagonist of prostaglandin E2. Using in vitro studies and a mouse xenograft model, we have subsequently shown that inhibition of COX-2 using indomethacin or siRNA-mediated knockdown results in inhibition of the CSC phenotype in glioblastoma, and enhances the efficacy of temozolomide chemotherapy in its treatment. We recently uncovered a direct interaction between PGE2 and Wnt signaling in GSCs, which have been shown to direct bone marrow regeneration following HSC ablation  and to be disregulated in acute lymphocytic leukemia. We have begun a collaboration with Dr. Cindi Morshead to examine this possible interplay of COX-2 and Wnt signaling in NSCs and glioblastoma.

Recent Publications

Das, S., Srikanth, M., and Kessler, J.A. (2008). Mechanisms of disease: cancer stem cells and glioma. Nature Rev Neuro 4: 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., and Bredel. M. (2009). Monosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas. JAMA 302: 276-289.

Goebeske, K., Das, S., Bonaguidi, M., Radulovic, J., Disterhoft, J., and Kessler, J. (2009). BMP signaling mediates effects of exercise on hippocampal neurogenesis and cognition. PLoS One 4: e7506.

Das, S. (2011). Cancer stem cells in adult gliomas. Atlas of Genetics and Cytogenetics in Oncology and Haematology. URL http://AtlasGeneticsOncology.org.

Mansouri, A., Fallah, A., Cusimano, M., and Das, S. (2012). Vasospasm post pituitary adenoma resection: systematic review 3 case presentations. Can J Neurol Sci 39: 767-773.

Mogu, T. and Das, S. (2013). Prostaglandins: Signal transduction cascades, cancer biology and therapeutic implications. J Canc Ther 4, 338-352.

Karamchandani, J., Wu, M., Das, S., Vogel, H., Muller, M., Cusimano, M., Montanera, W., and Kovacs, K (2012). Highly proliferative sellar chordoma with unusually rapid recurrence. Neuropathology 33: 424-430. doi: 10.1111/j.1440-1789.2012.01360.x.

Srikanth, M., Das, S., Kim, J., Berns, E.J., Stupp, S.I. and Kessler, J.A. (2013). Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stem-like cells to epidermal growth factor receptor inhibition. Neuro Oncol. 2013 Mar;15(3):319-29. doi: 10.1093/neuonc/nos316. Epub 2013 Jan 17.

Al-Omair, A., Soliman, H., Xu, W., Karotki, A., Mainprize, T., Phan, N., Das, S., Keith, J., Yeung, R., Perry, J., Tsao, M., and Sahgal, A. (2013), Hypofractionated cavity stereotactic radiotherapy (HCSRT) in five daily fractions for post-operative brain metastases patients with no prior and prior whole brain radiation. Technol Cancer Res Treat. 2013 Apr 24. [Epub ahead of print].

Schulte, J., Zhang, J., Adkins, J., Yin, L., Lathia, J., Srikanth, M., Das, S., Kessler, J., Muller, W., Olson, E., and Chenn, A. Cadherin11 regulates migration in cortical development and glioblastoma. Accepted to PLoS One.

Garavaglia, M.M., Hare, G.M.T., Tharmaradinam, S., Crescini, C., Mazer, C.D., Das, S. and Rigamonti, A. Anesthetic approach to high-risk patients and prolonged awake craniotomy using dexmedetomidine and scalp block. J Neurosurg Anesthesiol 2013 Sep 21. [Epub ahead of print].

Celebre, A., Danielson, B., Wu, M., Munoz, D., Das, S., and Karamchandani, K. Anaplastic meningioma with single cell infiltration: evidence of a role for the epithelial-mesenchymal transformation in progression of a meningoepithelial tumor. Accepted in Histopathology.

Das, S. and Marsden, P. Angiogenesis in glioblastoma: Cancer stem cells lead the charge. N Engl J Med 369: 1561-3. doi: 10.1056/NEJMcibr1309402.

Srikanth, M., Kim, J., Das, S., and Kessler, J.A. BMP signaling induces astrocytic differentiation of oligodendroglial stem–like cells. Accepted to Molecular Cancer Research.