The Molecular Underpinnings and Regulation of Amino Acid Pathways in Ewing sarcoma
Jimenez, Jennifer
2022
Abstract
Ewing sarcoma is an aggressive pediatric bone and soft tissue tumor, most commonly driven by EWS-FLI1. The standard of care for Ewing sarcoma has not improved in decades, and by far the best predictor of poor prognosis is the presence of metastases at diagnosis. However, regardless of disease presentation, both patients with localized and metastatic disease are treated with maximum doses of chemotherapy. The current treatment protocol has improved the survival rate for patients with localized disease to >70%; however, the outcome for metastatic patients is much less favorable with dismal survival rates of <20%. Furthermore, for survivors of the disease, the intense chemotherapy treatment leaves them with profound toxicities that follow them through life. To this day, the tumor-initiating EWS-FLI1 fusion protein is undruggable, thus it is imperative to better understand the biology of the disease in order to identify new vulnerabilities and develop better-targeted therapies. The disruption of cellular metabolism by oncogenic drivers is a hallmark of cancer, providing a therapeutic window for targeting dysregulated metabolism in the tumor. EWS-FLI1 rewires the metabolome by mechanisms that are not well understood. Previous work from our lab revealed that the scaffolding protein menin serves an oncogenic role in Ewing sarcoma, partly through regulation of amino acid metabolic pathways. In this thesis, I sought to investigate the molecular mechanisms by which amino acid pathways are dysregulated in Ewing sarcoma and to begin to evaluate targeting amino acid metabolism as a therapeutic vulnerability. Though transcriptomic analysis and molecular techniques, my work uncovered that EWS-FLI1 and menin both activate the master transcriptional regulator, ATF4. ATF4 functions to maintain cellular homeostasis, in part by upregulating amino acid biosynthetic pathways that support protein synthesis and proliferation, such as the serine biosynthesis pathway (SSP) and asparagine biosynthesis. Hyperactivation of the SSP has been extensively explored as a biomarker in Ewing sarcoma but its importance for driving tumorgenicity is not clear. We also discovered that inhibition of PHGDH partially antagonizes the EWS-FLI1-regulated gene signature, providing a possible explanation for dependence on high-level expression of PHGDH. Additionally, through the use of in vivo and in vitro models, we found that asparagine synthetase (ASNS) is robustly expressed in Ewing sarcoma and promotes metastatic progression. Mechanistically, this is due, at least in part, to significant changes in the expression of genes related to epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM). In conclusion, this thesis has elucidated that EWS-FLI1 and menin act to regulate ATF4 activity in Ewing sarcoma, in turn controlling amino acid metabolism pathways that impact metastatic progression. My studies thus highlight disease-driving exploitable metabolic vulnerabilities that may ultimately lead to better-targeted agents to reduce cytotoxic therapy or circumvent its need all together.Deep Blue DOI
Subjects
cancer biology pediatric cancer Ewing sarcoma metabolism epigenetics menin
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