Soft tissue sarcomas (STSs) are a highly diverse and understudied group of malignancies arising from mesoderm-derived tissues, where the cell of origin is unclear, but likely includes mesenchymal stem cells, muscle satellite cells and myoblasts. In the United States, nearly 20,000 individuals are diagnosed with STS, which is fatal for ~40% of patients due to either loco-regional recurrence or distant metastasis. Patients with undifferentiated pleomorphic sarcoma (UPS), the most aggressive sarcoma subtype, have a 5-year survival rate of only 24% with metastatic disease. Therefore, a deeper understanding of the mechanisms underlying UPS initiation and progression is critical to develop novel targeted sarcoma treatments, as well as improve the use of current therapies. Sarcomas, much like other solid tumors, typically thrive in hypoxic and/or nutrient poor conditions and to do so, implement adaptive mechanisms, which include the altered expression of hypoxia inducible factors (HIFs) that are stabilized under low O2 to promote survival in oxygen and nutrient limiting cellular environments. Notably, metabolic differences between normal muscle tissue and soft tissue sarcomas have been incompletely characterized, as well as the role of HIFs to alter STS metabolism. Data from The Cancer Genome Atlas demonstrate that sarcomas show significant changes in the expression of proteins involved in amino acid breakdown compared to normal skeletal tissue. The importance of muscle amino acid metabolism, particularly in maintaining whole body glucose homeostasis, is emphasized by the glucose-alanine cycle, which acts to transport amino groups and carbons from the muscle to the liver. Furthermore, the key transaminases involved in this pathway, glutamate-pyruvate transaminases (GPTs), are underexpressed in a number of STSs (including UPS) relative to normal skeletal tissue. Therefore, our central hypothesis of this proposal is that GPT s act as tumor suppressors by modulating amino acid and glycolytic metabolism in soft tissue sarcomas and adjacent normal muscle. Based on these hypotheses, I will pursue two specific aims.
Specific Aim 1 : determine the metabolic alterations in sarcoma progression and metastasis.
Specific Aim 2 : define the role of GPTs in mediating tumor growth in STS. To complete these studies, I will combine in vitro and in vivo methods of molecular biology, metabolomics, immunohistochemistry, animal modelling, and patient material. The overall objective of this proposal is to further our understanding of how metabolic alterations can promote sarcoma initiation and progression, which will help identify novel therapeutics targets to treat sarcoma patients.
Undifferentiated pleomorphic sarcoma (UPS) is one of the most aggressive and common soft-tissue sarcoma subtypes in adults. While the cell of origin is unclear, mesenchymal stem cells, muscle satellite cells and myoblasts have been implicated. As the normal muscle is important in regulating whole body metabolism, I propose to investigate metabolic alterations that can promote sarcoma initiation and progression in order to facilitate the development of novel targeted therapies for this disease.
| Hock, Andreas K; Cheung, Eric C; Humpton, Timothy J et al. (2017) Development of an inducible mouse model of iRFP713 to track recombinase activity and tumour development in vivo. Sci Rep 7:1837 |
