Lay Abstract
Cancer cells rewire metabolic pathways and energy production to support the enhanced proliferation, invasion and resistance to treatment. We recently found a remarkable enrichment of genes involved in hexosamine biosynthesis pathway (one of the glucose metabolism pathways) in a subset of leiomyosarcoma (LMS). We demonstrated that expression of GFPT2, the key enzyme of the hexosamine biosynthesis pathway, is associated with poor clinical outcome in LMS. Following the study on this pathway in LMS, we performed a large-scale immunohistochemistry screening of more than 30 different types of soft tissue tumors and we discovered nearly universal expression of GFPT2 in desmoid type fibromatosis (DTF). Our high-throughput transcriptomic analysis of DTF and 9 other types of fibrotic lesions identified significant enrichment of multiple genes implicated in hexosamine biosynthesis pathway in DTF compared to the other types of fibrotic lesions. We also found a candidate effector of the activation of this pathway in DTF, which may have a pro-oncogenic role and may be associated with resistance to treatment. Targeting hexosamine biosynthesis pathway was demonstrated to provide therapeutic benefit in a number of preclinical models of cancer. Thus, our preliminary findings provide a rationale to explore the potential of therapeutic targeting of the hexosamine biosynthesis pathway in DTF. The modulation of glucose metabolism through hexosamine biosynthesis pathway is a promising direction of research and our proposal offers the first functional exploration of the role of this pathway in DTF. Successful completion of this study will hopefully lead to novel therapeutic options for patients with DTF.
Scientific Abstract
Cancer cells rewire metabolic pathways and energy production to support the enhanced proliferation, invasion and resistance to treatment. The three main glucose metabolism pathways that support growth of cancer cells are: a) the glycolysis pathway for energy production; b) the pentose phosphate pathway for biomass production; and c) the hexosamine biosynthesis pathway (HBP) for protein glycosylation. Activation of HBP leads to altered glycosylation of oncogenes, transcription factors and kinases in many types of cancer. These aberrations contribute to increased proliferation and survival of tumor cells, and are associated with resistance to treatment. Therapeutic targeting of GFPT2 (glutamine-fructose-6-phosphate transaminase 2, the first and rate limiting enzyme in HBP) and other components of HBP exhibits anti-tumorigenic effect and modulates sensitivity to chemo-, radio- and immunotherapy. Most of the studies of HBP up to date focused on carcinomas and the role of HPB in sarcoma has not been extensively explored. We recently reported a remarkable enrichment of genes involved in HBP in a subset of leiomyosarcoma (LMS) and demonstrated that expression of GFPT2 in LMS is associated with poor clinical outcome. We identified the c-Myc oncoprotein as a potential target of HPB that may be stabilized by aberrant glycosylation in LMS.
In this application, based on exciting unpublished preliminary results, we propose a new direction of research related to metabolic reprogramming and glycosylation in desmoid type fibromatosis (DTF). Our initial data indicates that HBP may be activated in the majority of DTF. Our transcriptomic analysis of a dataset composed of DTF and 9 other types of fibrotic lesions identified significant enrichment of multiple genes implicated in HBP in DTF compared to the other types of fibrotic lesions. We also found that ATF6 transcription factor may be a candidate effector of the activation of this pathway in DTF. The goals of this proposal are: 1) to thoroughly characterize expression of the components of HBP in DTF, 2) to study the effect of perturbations of HBP in DTF cell lines, and 3) to explore therapeutic targeting of HBP in preclinical models of DTF. In this study, we will characterize protein expression levels of HBP components in well-annotated tissue microarrays with specimens of primary and recurrent DTF from over 210 patients, and in 13 primary DTF cell lines. We will also perform knock out and knock down of selected enzymes of HBP in primary cell lines derived from desmoid tumors and we will study the effect of these perturbations on cell growth, invasive properties, transcriptional profile, proteomic profile, and post-translational modifications by glycosylation. We will also perform pharmacological inhibition of GFPT2 and other components of HBP in cell line models to study the potential therapeutic benefit of this strategy in DTF. Our study will provide new insights into metabolic reprogramming and mechanisms of tumorigenesis in DTF. Our study will also explore the potential of therapeutic targeting of HBP in DTF. The modulation of glucose metabolism through HBP, either alone or in combination with other treatment modalities, is a promising direction of research and our proposal offers the first functional exploration of the role of this pathway in DTF. Successful completion of this study will hopefully lead to novel therapeutic options for patients with DTF.
