The focus of the research laboratory is on the biology of human translocation-associated sarcomas. These mesenchymal tumors are of special scientific interest because the fusion genes produced by these specific translocations pinpoint the oncogenic lesion central to their pathogenesis; thereby making them initially more tractable than other solid cancers. Some of the recurrent themes of the research program include translocation breakpoint cloning, biologic and clinical correlates of fusion gene structure and functional aspects of the chimeric transcription factors (CTFs) they encode, and defining transcriptional targets and expression profiles associated with these CTFs in sarcomas.
In the area of translocation breakpoint cloning, the laboratory has over the years cloned several novel fusion genes (EWS-WT1, ASPL-TFE3, etc.) and continues to perform the functional characterization of these CTFs (EWS-FLI1, ASPL-TFE3) and others (SYT-SSX). These fusions have also provided the basis for molecular diagnostic assays that have moved into clinical use. Our current focus in this area is in establishing and evaluating microarray-based approaches to the detection of novel genetic rearrangements in sarcomas and other cancers, based on high resolution copy number data and exon-level expression data.
Part of the laboratory's efforts have been concentrated on defining transcriptional targets and expression profiles associated with the CTFs of specific sarcomas. Large expression profiling datasets of translocation sarcomas have been generated and analyzed to identify new transcriptional targets of CTFs as well as new therapeutic targets and diagnostic markers. Our systematic unbiased approach to the identification of CTF target genes consists of a microarray-based screen for genes whose promoter regions are bound by the endogenous CTF in sarcoma cell lines, integrated with data on genes whose expression is altered upon induction of the same CTF in heterologous lines and whose expression shows evidence of similar regulation in tumor expression profiles. The role of these CTF target genes in the growth of the respective sarcomas is being evaluated by RNA interference screens.
A second area of work is in the cancer genomics of thoracic malignancies, specifically mesothelioma and lung adenocarcinoma. We have assembled large integrated datasets on gene expression and copy number for these cancers and these are being analyzed for correlations with known kinase mutations and correlations (in cell lines) with sensitivity to targeted therapies.
Finally, the laboratory also actively participates in several large scale collaborative cancer genomics efforts, including The Cancer Genome Atlas and the Sarcoma Genome Project, as well as mutational profiling projects based on the Sequenom mass spectrometry genotyping platform.
