Proteomic Analysis of Sarcoma: Molecular Differences between Benign and Malignant Tumors of Bone and Soft Tissue
The proteomic profiles of bone and soft tissue sarcomas remain largely unexplored. The “proteome” represents all protein isoforms expressed within a target tissue, including those with post-translational modifications. We are using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and liquid chromatography/tandem mass spectrometry (LC-MS/MS) to evaluate proteomic differences between selected sarcomas and their presumed benign counterparts and/or normal tissues. The specific aim of this proposal is to identify sarcoma-specific differences in protein expression that define the malignant phenotype. These findings may elucidate important mechanisms in sarcoma development and lead to novel diagnostic and therapeutic strategies.
Synovial sarcoma is a malignant soft tissue tumor marked by a unique t (X;18) translocation leading to expression of a chimeric SYT-SSX fusion protein. We have recently developed a mouse model of synovial sarcoma by expressing SYT-SSX fusion protein within myoblasts thereby identifying skeletal muscle lineage as a potential source of this disease. However, other potential sources of this disease remain an unknown possibility. The aim of this study is to use the mouse model to investigate the existence of other sources of synovial sarcoma and whether there is any correlation between clinical behavior of the tumor and its origin.
Osteosarcoma is 500 times more common in retinoblastoma patients compared to the normal population. The majority of osteosarcomas however do not occur as part of familial syndromes. The proposed research uses a novel 45Ca induced mouse model of osteosarcoma, as well as genome-wide transcriptional profiling and array-based comparative genomic hybridisation to identify genetics changes either unique or common to familial and sporadic osteosarcoma. These studies will identify pivotal genes and genetic changes, which initiate and allow progression of osteosarcoma in the presence and absence of Rb.
Study of the mechanisms of sarcoma progression using mouse models and in vitro manipulation of mesenchymal stem cells
The underlying genetic defects and the cell of origin of most human sarcomas remain unknown. Recently, alterations in the PI3K-Akt pathway have been identified in certain sarcoma subtypes. For instance, loss of heterozygosity of 10q (containing the PTEN genomic locus) has been frequently observed in human leiomyosarcomas (LMS). In addition, we have found evidences of PI3K/Akt constitutive signaling in human LMS. To determine the role of aberrant PI3K-Akt signaling in LMS pathogenesis, we have genetically inactivated Pten in the mouse smooth muscle (SM). Resultant animals carrying homozygous deletion of both PTEN alleles developed widespread SM hyperplasia, abdominal and retroperitoneal LMS… Read More »
Patients with metastatic osteosarcoma have a poor overall survival rate of 20%. The importance of stromal cells in the metastatic process is becoming well established. We have preliminary data to suggest that induction of genes in the stroma may contribute to metastasis in osteosarcoma. Our hypothesis is that the molecular signals that occur between osteosarcoma cells and the surrounding stromal cells lead to metastasis.
Rhabdomyosarcoma (RMS) is the third most common solid tumor in children and is often associated with high morbidity and mortality. The heterogenous nature of RMS along with the lack of genetically accurate mouse models has precluded this cancer from many of the therapy testing strategies currently being used for other malignancies. We hope to develop a mouse model that will accurately recapitulate the human disease including genetic heterogeneity and metastatic potential. These mice will allow testing for further classification of tumors that will aid in treatment decisions and be use to test novel therapies in pre-clinical trials for RMS treatment.