Research Project

Website: www.cancerstemcells.ca

Summary

Brain tumours, breast cancer, and leukaemia are among the most common and lethal cancers that affect Canadians. Because they frequently affect young women and children, many patients receive very aggressive treatments to improve their chances of survival. But these treatments often have serious side effects, and they are not effective in fighting the most serious forms of these cancers.

According to project leader Dr. Cynthia Guidos, a Senior Scientist at the Hospital for Sick Children Research Institute in Toronto and a Professor of Immunology at the University of Toronto, treatment may fail if the therapy does not target the rare cancer stem cells, which can reinitiate the growth of the tumour and thus function as its ‘roots.’

The research of Dr. Guidos’ team focuses on the development of normal and leukaemic immune cells. Her team also includes experts in brain tumours, breast cancer, cancer stem cells, and leukaemia. The project team is studying human tumours and mouse cancer models in order to address two crucial issues: what genetic alterations distinguish very aggressive from more benign tumours, and what genetic and biological malfunctions lead to development of cancer stem cells?

By dissecting the cellular signals that govern abnormal survival of tumour and cancer stem cells, researchers hope to develop new ‘biomarkers’ that may help doctors to reserve the most aggressive cancer treatments for patients most likely to fail conventional therapies. Ultimately, the project may lead to new and more effective therapies targeting cancer stem cells. The team hopes that its research will eventually increase survival rates and improve quality of life for survivors of brain tumours, breast cancer, and leukaemia.

Significant Outcomes to Date

• Discovery of a gene with properties that allow for the successful engraftment of stem cells from human bone marrow into mice (see reference below, Takenaka 2007). This discovery may lead to the development of therapies to increase the success rate of bone marrow transplants in human patients.
• First identification of cancer stem cells in colon cancer (see reference below, O’Brien 2007).
• Development of a new mouse model for leukemia that can be used to identify human leukemia stem cells and study how these cells change as the disease progresses (see reference below, Barabe 2007).
• Discovery of an oncogenic mutant of the Flt3 receptor tyrosine kinase, which causes leukemia and helps the cancer spread to the central nervous system.
• Discovery that the anti-fungal agent Ciclopirox Olamine induces cell death in leukemia and myeloma cells and greatly reduces the spread of leukemia to the central nervous system and other organs (see reference below, Eberhard 2009).
• Revision of the map of blood cell development, which now shows the origin of macrophages and dendritic cells in early lymphoid development (see reference below, Doulatov 2010).
• Demonstration that for BCR-ABL1 lymphoblastic leukemia, several genetically distinct lineages of cancer stem cells exist and that poor patient outcome is associated with deletion of CDKN2A and CDKN2B. This study highlights the clonal diversity of cancer stem cells, the complexity of the disease, and the need to develop therapies that eradicate all intra-tumoral sub-clones of cancer stem cells (see reference below, Notta 2010).

Notable Publications

Takenaka, K, Prasolava, TK, Wang, JC, Mortin-Toth, SM, Khalouei, S, Gan, OI, Dick, JE, and Danska, JS. 2007. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat. Immunol. 8(12): 1313-23.

Barabe F, Kennedy JA, Hope KA, and Dick JE. 2007. Modeling the initiation and progression of human acute leukemia in mice. Science.316(5824):600-4.

O’Brien C., Pollett A, Gallinger S, and Dick J. 2007. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 445(7123): 106-10.

McKenzie JL, Gan OI, Doedens M, Wang JCY and Dick JE. 2006. Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment. Nat. Immunol. 7(11): 1225-33.

Dirks P. 2006. Stem Cells and Brain Tumors. Nature. 444:687-8.

Kennedy JA, Barabe F, Patterson BJ, Barber DL, and Dick JE. 2006. Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo. Proc Natl Acad Sci USA. 103: 16930-5.

Dufner A, Pownall S, and Mak TW. 2006. Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-kappaB activation. Proc Natl Acad Sci USA. 103: 988-93.

Yanina Eberhard, Sean McDermott, Xiaoming Wang, Marcela Gronda, Amudha Venugopal, Tabitha E. Wood, Rose Hurren, Alessandro Datti, Robert A. Batey, Jeff Wrana, William E. Antholine, John Dick, Aaron Schimmer. 2009. Chelation of intracellular iron with the anti-fungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood. 114: 3064-3073.

Doulatov S, Notta F, Eppert K, Nguyen LT, Ohashi PS, and Dick JE. 2010. Revised map of the human progenitor hierarchy reveals the origin of macrophages and dendritic cells in early lymphoid development. Nat. Immunol. 11: 585-93.

Notta F, Mullighan CG, Wang JC, Poeppl A, Doulatov S, Phillips LA, Ma J, Minden MD, Downing JR, and Dick JE. 2011. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature. 469: 362-7.