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Stem Cells - Differentiation, Plasticity and Senescence in Cancer

Stem Cells - Differentiation, Plasticity and Senescence in Cancer

Thursday, March 29, 2007

The New York Academy of Sciences

Presented By


Speakers: John Dick, University of Toronto; Michael Clarke, Stanford University; Erica Herzog, Yale University; David Scadden, Harvard University; Ihor Lemischka, Princeton University

Organizer: Jonathan Licht, Northwestern UniversityThe Cancer and Signaling Discussion Group provides a forum for an exploration of the molecular networks that ensure proper cell cycle progression and how alterations in these networks modulate gene expression, cause mutations, and fuel the steps involved in carcinogenesis. Meetings of the group will focus on specific themes as they relate to signal transduction dysregulation in oncogenesis and will cover basic, clinical and diagnostic aspects of the field.

1:00-1:05 pm
Jonathan Licht, MD

1:05-1:45 pm
Cancer-initiating cells: From Leukemia to Solid Tumors
John E. Dick , PhD

1:45-2:25 pm
Self Renewal in Normal Tissues and Cancer
Michael F. Clarke, MD

2:25-3:05 pm
Lost and Con-fused: Y Does it Matter, or, Marrow Derived Lung Epithelium Following BMT and Pneumonitis
Erica Herzog, MD, PhD

3:05-3:30 pm
Coffee Break

3:30-4:10 pm
Cancer and the Niche Hypothesis
David Scadden, PhD

4:10-4:50 pm
Dissecting Cell Fate Regulation in Stem Cells
Ihor Lemischka, PhD

4:50-5:00 pm
Closing Remarks

5:00-6:30 pm


Cancer-initiating cells: From Leukemia to Solid Tumors
John E. Dick , PhD
Division of Cell and Molecular Biology, University Health Network
Department of Medical Genetics and Microbiology, University of Toronto

Two fundamental problems in cancer research are identification of the normal cell within which cancer initiates and identification of the cell type capable of sustaining the growth of the neoplastic clone. There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. What is less clear for most cancers is which cells within the tumor clone possess tumor initiating or "cancer stem cell" (CSC) properties and are capable of maintaining tumor growth. In the last decade there has been progress to identify the CSC of some hematologic and solid cancers. An appreciation of the biological distinctness of CSC is crucial not only for the design of studies to understand how tumourigenic pathways operate, but also for the development of specific therapies that effectively target these cells in patients. Studies of human acute myeloid leukemia are the most advanced but cancer initiating cells have now been identified in a number of solid tumours.

Our studies have demonstrated that LSCs are not functionally homogeneous but, like the normal hematopoietic stem cell (HSC) compartment, comprised of distinct hierarchically arranged LSC classes. Distinct LSC fates derived from heterogeneous self-renewal potential. Thus, the AML clone is organized as a hierarchy that originates from SL-IC, which produce AML-CFU and leukemic blasts. Available evidence from murine studies suggest that both normal HSC and/or progenitors represent the target cell of origin depending on the oncogene; the human equivalent is unknown. Although the association of oncogene expression and human leukemia is strong, conclusive evidence that one or more oncogenes can transform a normal human blood cell into a fully leukemic cell is lacking. We have found that expression of MLL-ENL in lineage-depleted cord blood cells followed by transplantation into sub-lethally irradiated NOD/SCID mice resulted in the development of an aggressive human pro-B acute lymphoblastic leukemia (ALL) characterized by the extensive accumulation of immature B cells in the bone marrow and organs in less than 18 weeks. Another MLL fusion, MLL-AF9 yielded mice with AML or pre-B ALL. Clonal analysis of retroviral insertion and Ig rearrangement that the LSC varies amongst mice ranging from multipotential HSC to more committed lymphoid progenitors but not mature B cells, providing insight into the target of the transfo