Dr. Ogilvie – Research Grant – 2011

Dr. Tamra Ogilvie, an Assistant Professor in the Regenerative Medicine Program in the Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba

Project Title: “Comparing the stem cell properties of the most invasive and non-invasive malignant brain tumour cells.”

Research Summary:

Dr. OgilvieThe existence of a brain tumor stem cell has changed how we think about cell-specific targeted therapies; however, several issues still plague current cancer stem cell theory. For example, it is not known whether brain tumor stem cells are directly responsible for recurrence of the most aggressive tumors such as the adult glioblastoma multiforme (GBM) and pediatric medulloblastoma. My labratory is interested in evaluating the relationship between the invasive and stem cell properties of primary malignant brain tumors.

Using a variety of techniques, the proposed study involves isolating and expanding individual cell clones from GBM and medulloblastoma cell lines. 3-dimensional tumor spheres will be prepared and implanted into a collagen matrix, used as a surrogate for infiltration of tumour cells in the brain. Invasive and non-invasive clones will be selected for further analysis. Both the functional and molecular stem cell properties will be compared between invasive and non-invasive malignant brain tumour clones.

Since the highly infiltrative nature of malignant brain tumors is a major factor in poor patient prognosis, a more comprehensive understanding of their stem cell properties will shed light on the true correlation of a “brain tumor stem cell phenotype” with clinical outcome.

Research Outcome:

We have recently identified a “marker”, called CD271, on the surface of medulloblastoma cells that help define the most immature tumor-maintaining cells called “stem cells”. Using these cellular “fingerprints”, we were able to pluck the stem cells from a larger, more diverse cell population in a dish. Our results also suggest that this marker may be specific to one of the medulloblastoma subtypes. Now, we are investigating whether other markers, in addition to CD271, can be used to select for medulloblastoma cell populations that will both initiate and maintain tumor growth in a dish and a mouse model of the disease. In addition, we would also like to identify fast moving cells that escape current treatments and contribute to tumor recurrence.

This will enable us to move forward with drug discovery studies where we hope to target cells with a stem cell or fast moving, mobile cell signature in a more specific manner. Concurrent targeting of multiple cell types would make medulloblastoma and other pediatric brain tumours much more manageable, thereby lessening the impact of harsh, toxic therapies such as radiation and chemotherapy on the developing nervous system of child patients.

Further update:

When you think of fingerprinting, CSI and other crime shows might be what come to mind. But it’s the idea of this forensic practice (identifying individuals by the distinctive make-up of their prints) that plays a major role in Dr. Tamra Ogilvie’s work.

Tamra was a recipient of a 2011 Brain Tumour Research Grant for her project that explores the relationships between different types of tumour cells in pediatric medulloblastoma, the most common form of childhood brain cancer. The two varieties of cells included in Tamra’s study are stem (cells involved at the start of tumour development) and invading (cells that infiltrate the normal tissue around the tumour).

“By looking at stem and invading cells we can determine their ‘fingerprints,’ essentially identifying cell types by the unique characteristics on their surface,” she explains. “We can then better assess how different combinations of these markers can select cells that impact the growth and spread of the tumour.”

In her Winnipeg, MB lab, Tamra grows clones of tumours from large cell populations as well as recent patient-tissue derived stem cells. She then screens the clones for biomarkers to determine the difference between the most and least invasive cells, and if there were specific markers that could predict their behaviour.

Since her research began, Tamra has identified a combination of three biomarkers within medulloblastoma that mark a particular cell type. This is a critical finding that further progresses her study as Tamra’s team is now looking at how different combinations of these markers impact the growth pattern of medulloblastoma and how future treatment options can better target tumours that have a mix of these markers.

“Since chemo only targets growing cells, some stem and invading cells are resistant because they aren’t dividing as quickly. We have a lot of variability with medulloblastoma and need more than one drug to attack these cells.”

When asked what she hopes her research will lead to in the future, Tamra says it’s the prospect of novel treatments that helps drive her study, treatments that will be more effective than traditional chemotherapy or radiation since the future therapies would be more individualized. “We want to use this cellular fingerprinting to improve drug screening and discovery, pinpointing treatments that better target the specific mix of cells within the tumour, leading to better quality of life for the patient.”

Dr. Ogilvie’s Research Update – July 2013

Brain tumours are among the most common forms of childhood cancer. Medulloblastoma is the most common malignant primary pediatric brain tumour and recent evidence has demonstrated that there are 4 very distinct subtypes that will likely require different treatments. Despite a 5-year survival rate of 60-70%, these tumours are highly aggressive and frequently recur following chemotherapy or radiation resulting in a poor prognosis.

We have recently identified a “marker”, called CD271, on the surface of medulloblastoma cells that help define the most immature tumour-maintaining cells called “stem cells”. Using these cellular “fingerprints”, we were able to pluck the stem cells from a larger, more diverse cell population in a dish. Our results also suggest that this marker may be specific to one of the medulloblastoma subtypes. Now, we are investigating whether other markers, in addition to CD271, can be used to select for medulloblastoma cell populations that will both initiate and maintain tumour growth in a dish and a mouse model of the disease. In addition, we would also like to identify fast-moving cells that escape current treatments and contribute to tumour recurrence.

This will enable us to move forward with drug discovery studies where we hope to target cells with a stem cell or fast-moving, mobile cell signature in a more specific manner. Concurrent targeting of multiple cell types would make medulloblastoma and other pediatric brain tumours much more manageable, thereby lessening the impact of harsh, toxic therapies such as radiation and chemotherapy on the developing nervous system of child patients.

Publications

Deconstruction of Medulloblastoma Cellular Heterogeneity Reveals Differences between the Most Highly Invasive and Self-Renewing Phenotypes
Ludivine Coudière Morrison, Robyn McClelland, Christopher Aiken, Melissa Bridges, Lisa Liang, Xin Wang, Domenico Di Curzio, Marc R. Del Bigio, Michael D. Taylor, and Tamra E.Werbowetski-Ogilvie
April 2013
Neoplasia