The SARC™ Lab, a division of sarcoma services, is a translational and basic science research laboratory specializing in the molecular genetics of sarcomas and related diseases. The SARC™ Lab routinely employs molecular (e.g., cDNA gene expression profiling, RT-PCR, western blots, etc.) and cell biology (viability assays, apoptosis, etc.) techniques and assays to address questions pertaining to the molecular classification and biology/pathogenesis of sarcomas and mesenchymal neoplasia. In order to fulfill this goal, we also use a variety of specialty core facilities (CF) maintained by the University of Utah, including the Microarray CF, the Genomics CF, the Flow Cytometry CF, and the Protein/Peptide CF.
Our main areas of research include the following:
cDNA Microarrays and Gene Profiling
Sarcomas are cancers of connective tissue or mesenchyme. While approximately 10,000 sarcomas are diagnosed per year in the United States, greater than 50% of patients will die from the disease. Currently applied diagnostic techniques using morphology, histology, immunohistochemistry, and cytogenetics are inadequate. Because diagnostic discrepancy can exceed forty percent, a better system of classification is imperative in order to improve outcomes for these frequently morbid and often deadly tumors. To truly understand the neoplastic process in mesenchymal tissues, one must first improve diagnostic criteria to better classify and stratify the greater than three hundred entities. In the future, molecular phenotyping will become commonplace. Modalities such as cDNA and in situ microarrays, proteomics and hybrid techniques will complement and perhaps replace methods utilized today.
Our long-term goal is to develop a mesenchymal tumor classification system based on cDNA profiling of actual tumors evaluated ex vivo. Our rationale is based on evidence that different profiles of mRNA expression reflect differences in the biological properties of cancer. Identifying signature patterns of gene expression via cDNA profiling may supersede the prognostic ability of histologic subtype, grade, anatomic location, and the presence or absence of particular characterized, solitary molecular aberrancies such as translocations. cDNA microarrays facilitate the systematic and comprehensive analysis of transcriptional alterations occurring in diseased tissues. This technique involves quantitative hybridization to a large panel of cloned genes with the total expression complement (cDNA) derived from a particular cell or tumor. We realize that cDNA arrays in isolation may tell us nothing about sarcoma pathogenesis as it does not address protein-driven issues. A given expressed gene does not necessitate that the protein product is integral to the process of sarcomagenesis. Nevertheless, this protein may be specific to the tumor, thereby facilitating classification but providing no information as to the mechanisms of pathogenesis. The information generated by microarray projects will complement and incorporate data created via proteomics, in situ microarrays, hybrid and other techniques. Only after learning the relationship of these tumors to normal mesenchyme can we then begin to predict their behavior and elucidate the mechanisms of their pathogenesis.
Programmed Cell Death (Apoptosis in Sarcomas)
Apoptosis, or programmed cell death, is a part of the normal life cycle of many, perhaps all, cell types and has emerged as a very important regulatory pathway in oncogenesis and in the pathogenesis of many human diseases. Apoptosis is used for the systematic elimination of excess, damaged, or hazardous somatic cells. It is a process by which the cell commits to cellular suicide in a systematic, highly energy dependent method of disassembly and packaging. Facilitating apoptosis selectively in the cancer cell is a mechanism by which oncotherapy may prove highly advantageous. Unfortunately, punctilious pursuit in understanding programmed cell death and the factors that influence it, even in the normal cell, has been a challenge. Conceptually, however, if an optimal understanding of the extrinsic (Fas-induced) apoptotic pathway can be garnered, with therapeutic targets revealed, a combined pro-death and anti-life clinical approach can be tailored to the renegade cancer cell. Our long-term goal is to facilitate the development of new pro-apoptotic targets in the bio-targeted treatment of mesenchymal neoplasia, and specifically sarcomas, by improving the understanding of the regulation of the extrinsic Fas ligand mediated death pathway. Initially, by fastidiously investigating the details of whether the FasL/EGFR/Fas relationship applies to mesenchyme, as described in hepatocytes (and hepatocellular carcinoma), we can establish a detailed working model of extrinsically induced apoptosis in mesenchymal neoplasia. As CTGF is known to positively affect fibroblastic proliferation, we will also gain an understanding of how this mesenchymal growth factor influences the FasL-mediated apoptotic pathway in sarcomagenesis. Only by understanding the details of these relationships can we then move forward, in partnership with medicinal chemistry, to specifically target these complex neoplastic pathways via a multi-interference approach.
Cartilaginous lesions of bone are relatively common, and cover a large spectrum, from the benign enchondroma to the aggressive dedifferentiated chondrosarcoma. Differentiating between these lesions, particularly benign enchondroma and low-grade chondrosarcoma, can be quite challenging. This involves the assimilation and interpretation of clinical, radiographic, and histologic criteria. Molecular techniques to assist in distinguishing between the various subtypes are being developed, but have as yet not yielded any clinically significant contribution. Our lab, in conjunction with an international, cooperative chondrosarcoma clinical trial developed at HCI, uses cDNA microarray profiles to distinguish enchondroma from low-grade chondrosarcoma in an effort to better elucidate the diagnosis, prognosis, and eventual therapeutic interventions for cartilage cancer.
The SARC Lab is a subsection of the comprehensive, interdisciplinary Sarcoma Services at Huntsman Cancer Institute and Primary Children's Medical Center. The clinical service line serves as a major referral center for sarcomas and sarcoma-related diseases from throughout the western United States and beyond. Multiple IRB approved clinical studies are underway, and the SARC Lab serves as a resource for the translational ramifications of these investigations. Furthermore, with patients' fully informed consent, all relevant surgical specimens retrieved at the time of surgery at our centers are made available to the lab for genetic profiling to elucidate a better classification schema and understanding of the pathogenesis for these rare but potentially deadly tumors.