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“If cancer stem cells lie at the heart of some cancers, then being able to predict the behavior of tumors and providing effective therapies against them means understanding the abnormal growth pathways within the stem cells themselves.”
- John Dick, Project Leader (UHN)
“The only reason that I'm willing to take a risk on this project is my confidence in the quality and camaraderie of my colleagues.”
- Scott Tanner, Principal Investigator (University of Toronto)
“We're examining DNA not for its well-recognized role as the genetic material to store and transmit genetic information, but rather for its less-known potential to act as a novel cancer diagnostic tool.”
- Yingfu Li, Principal Investigator (McMaster University)
“We're gaining more understanding of cell defects and how to modify them, so that treatment is no longer a shotgun approach, but more like an arrow aimed at a specific target.”
- Mark Minden, Principal Investigator (OCI)
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The principal task of Dr. John Dick's lab at the University Health Network (Toronto General Research Institute) will be to isolate the most primitive leukemic stem cells and hematopoietic stem cells possible using the currently-defined set of cell surface antigens, and to identify candidate biomarkers that may be used to further classify those stem cell populations.
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Hematopoietic stem cells (HSCs) are the cells that are responsible for building and sustaining the normal human blood system. When HSCs divide, they can replicate themselves or they can differentiate and become another cell type. Through multiple rounds of proliferation and differentiation, HSCs can create all of the cell types that make up human blood.
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Leukemic stem cells (LSCs) are the cells that are responsible for building and sustaining leukemias. Even though LSCs are only present at a rate of 1 in one million cancer cells in leukemia patients, LSCs are fundamental to sustaining the cancer, and eliminating LSCs from the body is essential to eradicating leukemia.
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A biomarker is a molecule that is characteristic of a given cell type or biological state. Often, biomarkers are proteins.
The long-term objectives of our research program are to understand the organization and developmental program of human hematopoietic stem cells, and to characterize how altered expression of key regulatory genes leads to leukemic transformation.
We have developed novel in vivo assays for normal human hematopoietic stem cells by transplantation of normal human bone marrow or cord blood into immune-deficient mice (the NOD/SCID repopulation assay). Because the mice are immune-deficient, their bodies do not reject the transplanted human cells. Instead, the human stem cells are able to grow, divide and differentiate into all of the cell types normally found in human blood, and we are able to observe the process. In addition to normal cells, we have established a NOD/SCID mouse model of human leukemia that is analogous to the progression of the disease in humans.
We have also developed a system to genetically manipulate human hematopoietic cells with retrovirus vectors expressing human growth regulatory genes and oncogenes. This will enable us to mark stem cells (and their progeny) to follow their lineage development, and to abnormally express a variety of growth regulatory genes to determine their role in the stem cell developmental program.
Using these technologies in combination, we will isolate hematopoietic and leukemic stem cells that are as primitive (undifferentiated) as possible. The gene expression in the two classes of cells will be compared (in Dr. Mark Minden's lab), and we will use this data to select combinations of proteins whose expression could uniquely identify either HSCs or LSCs within a complex mixture of cells. Dr. Yingfu Li's lab will use these proteins as targets for aptamer development, resulting in a suite of reagents that can be used to study the differences between LSCs and HSCs and to identify them in biological samples.
Lapidot, Nature 1994
Bonnet, Nature Med 1997
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