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Stephen Lessnick

Assistant Professor of Oncological Sciences and of Pediatrics

B.A. Brandeis University

M.D./Ph.D. University of California, Los Angeles

Research

References

stephen.lessnick@hci.utah.edu

Stephen Lessnick's Lab Page

Research

Cancer in adults is thought to occur through an accumulation of mutations in a single cell.  Mathematical and experimental modeling has suggested that 4-7 mutational “hits” are required for the development of most adult tumors.  Because time is required for the accumulation of mutations, the incidence of cancer increases with age.

Cancer in children is very different from cancer in adults.  For example, children get different types of cancers than adults do.  Adult cancers are often genetically unstable, while pediatric cancers are not.  Finally, the age distribution of pediatric versus adult tumors is distinct.  These and other data raise the possibility that pediatric tumors do not occur as a simple consequence of an accumulation of mutations.

We are focusing on Ewing’s sarcoma as a prototypic pediatric cancer.  Ewing’s sarcoma is a pediatric tumor of uncertain histologic origin that is defined by the presence of a specific chromosomal rearrangement, t(11;22)(q24;q12).  This translocation generates the EWS/FLI fusion oncogene.  EWS/FLI functions as an aberrant transcription factor to dysregulate gene expression.  The genes that are dysregulated by EWS/FLI are likely to be involved in Ewing’s sarcoma development.  Until recently, the genes that are altered by EWS/FLI, and their roles in Ewing’s sarcoma development were largely unknown.

We have developed a unique system to study the function of EWS/FLI, and its target genes, in Ewing’s sarcoma itself.  We have been using retroviral mediated RNAi to “knock-down” EWS/FLI expression, and then using oligonucleotide microarrays to identify the genes that are altered.  In this way we have identified many genes whose expression is dependant on the fusion protein.  We have been analyzing these genes for their role in oncogenic transformation using a variety of tools, including knockdown with RNAi, expression of dominant-negatives, and overexpression.  Phenotypic consequences are analyzed using a variety of techniques including soft-agar assays and xenografts to assess oncogenic transformation.  The ultimate goal of these experiments is to develop a comprehensive understanding of the transcriptional program triggered by EWS/FLI, and how that program leads to cancer.

Related to these efforts, we are also studying the impact of disrupting the EWS/FLI-mediated transcriptional program.  For example, drugs which block the activity of EWS/FLI itself, or which block the activity of its downstream effectors, appear to inhibit the transformed phenotype of Ewing’s sarcoma cells.  These drugs are then candidate therapeutics for patients with this disease.  We hope that further integration of our developing molecular understanding of this disease with therapeutic efforts will improve the care of children with this disease.  Furthermore, we believe that a deeper understanding of Ewing’s sarcoma development will reveal fundamental mechanisms involved in a variety of pediatric cancers.

The left panel shows patient-derived Ewing’s sarcoma cell lines growing as xenografts in immunodeficient mice.  The cells have been engineered to express the luciferase cDNA.  Administration of the substrate for luciferase to the mice causes the injected tumor cells to produce light via bioluminescence.  This light can be imaged by a sensitive CCD camera to demonstrate growth of the tumors.  We plan to remove these tumors and assess their gene expression patterns using oligonucleotide microarrays (right panel) to identify genes that are involved in the metastatic phenotype.

References