Functional Genomics of Sarcoma

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Our laboratory has had a long-standing interesting sarcoma genome biology. Our recent efforts are focused on the investigation of important emerging aspects of pediatric and adult sarcoma multi-omics analyses. We have investigated the molecular consequences of specific mutations which occur in sarcoma, particularly the common chromosome translocations which produce the fusion gene transcription factors characteristic of several pediatric sarcomas. Using chromatin immunoprecipitation and DNA sequencing technology (ChIP-Seq), we have identified the binding sites of oncogenic transcription factors and integrating this information with the known expression profiles of these diseases. In Ewing sarcoma, we have also used RNA interference technology to target the oncogenic transcription factor EWS-FLI1 to study the genes regulated by this protein. In alveolar rhabdomyosarcoma we have used ChIP-Seq to identify the genes which are targeted by the oncogenic fusion protein PAX3-FKHR. This has provided the framework for building the network of dysregulated genes downstream of these critical oncogenic events. Currently our efforts are focused on pursuing leads arising from studies of two sarcomas important in pediatric oncology, osteosarcoma and SDH deficient gastrointestinal tumors. Because of the highly chaotic nature of the osteosarcoma genome, prioritizing candidate genes for investigation is challenging. Osteosarcoma cell line models capture many aspects of this process providing a platform for functional investigations. These models also can be useful for study aspects of chromosome biology and genome instability. For example, we recently determined that osteosarcoma cells often maintain their telomeres through the Alternative Lengthening of Telomeres Pathway (ALT). We developed a model system in a cell line that has a defect in the DAXX gene as the molecular basis of its ALT phenotype by modifying these cells to allow the inducible suppression and re-expression of ALT. Using cell line models, we are using multi-omics approaches to define the events that occur with transition to and from the ALT state. Similarly, using cell line models, we are investigating the functional properties of a novel target for immunotherapy with antibody-drug conjugates, LRCC15. We have recently reported the activity if an LRRC15 ADC in osteosarcoma cell line xenografts and established that high LRRC15 expression can be induced even. in cell lines with low baseline expression. To gain a comparative genomics perspective on this disease, we have also investigated the gene expression pattern of canine osteosarcoma, and plan to take advantage of the similarities between human and canine disease to refine our understanding of this tumor. In gastrointestinal stromal tumor, we have focused on the group of tumors which lack mutations in signal transducing kinases. We have previously found that this group of tumors, uniformly characterized by lack of succinate dehydrogenase, demonstrates striking global abnormalities in DNA methylation. Recently we established that a subset of gastrointestinal tumors silence SDHC through DNA methylation in the absence of DNA mutation (termed epimutation). This provided a new insight into the mechanism of disease.