Education:
BSc 1986 - McMaster University, Hamilton, Ontario
MD 1989 - McMaster University, Hamilton, Ontario
PhD 2002 - University of British Columbia, Vancouver
Postdoctoral Research Fellowship:
1994-1996 University of British Columbia
1996-2002 University of British Columbia
2001-2003 University of California, San Francisco
Started at USC: 2004
Research Topics: Cancer Cell Biology, Cancer Genetics, Stem Cell Biology, Cell Death
Research Description
Evaluating the consequences of EWS-FLI1 oncogene expression on stem cells and the developing neural crest.
Despite advances in other areas of cancer research the prognosis for children diagnosed with bone and soft tissue tumors, such as Ewing’s sarcoma, remains poor. Members of Ewing’s sarcoma family tumors (ET) express disease-specific fusion-genes that are formed as a consequence of chromosomal translocations. These genes, including the most common version EWS-FLI-1, encode novel chimeric proteins that are oncogenic. The molecular mechanisms of EWS-FLI-1-induced malignant transformation remain elusive, although it likely disrupts both transcription and mRNA splicing.
The cell of origin of ET is not known, hindering the development of both in vitro and in vivo models. The accumulated evidence suggests that ET arises from a stem or progenitor cell in early neural crest or mesenchyme development. In my laboratory we are using both lineage-restricted and embryonic stem cells to develop novel models in which to study the effects of EWS-FLI1 and its downstream effectors, such as the cMyc proto-oncogene. Using genetically modified stem cells and inducible expression constructs, we are able to kinetically evaluate the effects of oncogene activation at discrete timepoints during in vitro and in vivo differentiation assays. These systems permit real-time detection of changes in normal proliferation, apoptosis, and differentiation that occur as a consequence of EWS-FLI-1 or cMyc activation. Assessment of these processes in these biologically relevant cell-types, in 3-dimensional spheroids, at physiologic oxygen concentrations provides a contextual environment that closely recapitulates that of ET tumorigenesis in humans.
Normal stem cells exhibit the capacity for self-renewal, a feature that is shared by cancer stem cells. The polycomb gene family member Bmi1 is integral to the self-renewal of hematopoietic, neural and neural crest stem cells as well as some leukemia stem cells. Its mechanism of action is via direct transcriptional suppression of the Cdkn2a locus, which encodes both p16INK4a and p14ARF. Suppression of Ink4a and ARF expression suppress activation of the Rb and p53 pathways, respectively, and therefore facilitate proliferation and survival whilst preventing senescence. We have shown that ET expresses Bmi1 and that its level of expression correlates with that of EWS-FLI1. We are now evaluating whether Bmi1 co-operates with EWS-FLI1 in malignant transformation and whether it is necessary for ET cell self-renewal and tumorgenicity. It is our hypothesis that Bmi1 expression is a clue to the cell of origin of ET and that it may be a marker of an ET stem cell.
The proto-oncogene cMyc is implicated in the induction of the neural crest and in the regulation of its normal development. cMYC is a downstream target of EWS-FLI-1 and therefore, EWS-FLI-1 expression in the developing neural crest may disrupt normal tissue differentiation and development, in part, through deregulation of cMYC. cMYC-induced tumor formation is complex and incompletely understood but clearly involves destabilization of the intricate balance between Myc-induced proliferation and Myc-induced apoptosis. We are interested in the relationship between EWS-FLI-1 expression and cMYC deregulation in the origins of ET, in particular in the context of the developing neural crest.
Selected Publications
Coles EG, Lawlor ER, Bronner-Fraser M. - EWS-FLI1 Causes Neuroepithelial Defects and Abrogates Emigration of Neural Crest Stem Cells. - Stem Cells [ 2008 ] Jun 12; . PubMed
Meyer JS, Nadel HR, Marina N, Womer RB, Brown KL, Eary JF, Gorlick R, Grier HE, Randall RL, Lawlor ER, Lessnick SL, Schomberg PJ, Kailo MD. - Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. - Pediatr Blood Cancer [ 2008 ] Aug;51(2):163-70 . PubMed
Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI. - Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. - Nat Med [ 2007 ] Oct;13(10):1211-8 . PubMed
Shchors K, Shchors E, Rostker F, Lawlor ER, Brown-Swigart L, Evan GI. - The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta. - Genes Dev [ 2006 ] Sep 15;20(18):2527-38 . PubMed
Lawlor ER, Soucek L, Brown-Swigart L, Shchors K, Bialucha CU, Evan GI. - Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis. - Cancer Res [ 2006 ] May 1;66(9):4591-601 . PubMed
Christophorou MA, Martin-Zanca D, Soucek L, Lawlor ER, Brown-Swigart L, Verschuren EW, Evan GI. - Temporal dissection of p53 function in vitro and in vivo. - Nat Genet [ 2005 ] Jul;37(7):718-26 . PubMed
