Background: mTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS). Methods: Human tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media.13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling. Results: Asn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth. Conclusions: Asn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS.
背景：mTORC1的活性依赖于包括天冬酰胺（Asn）在内的微量营养素存在，以促进多种癌症中的合成代谢细胞信号传导。我们假设，通过靶向天冬酰胺代谢来降低高分化（WD）/去分化（DD）脂肪肉瘤（LPS）中的mTORC1活性，从而抑制肿瘤生长。方法：利用人类肿瘤代谢组学分析比较WD与DD LPS中天冬酰胺的丰度。基因集富集分析（GSEA）比较了DD与WD LPS中上调的代谢通路之间的相对表达。通过使用电子传递链（ETC）抑制剂与无天冬酰胺培养基的联合处理，对LPS细胞系和类器官模型进行增殖实验。13C-葡萄糖标记代谢组学评估了联合处理对核苷酸合成的影响。利用小鼠异种移植模型评估ETC抑制与聚乙二醇化L-天冬酰胺酶（PEG-Asnase）联合使用对肿瘤生长和mTORC1信号传导的影响。结果：与WD LPS相比，DD LPS中天冬酰胺富集。GSEA表明，mTORC1信号传导在DD LPS中上调。在可用的LPS细胞系和类器官模型中，ETC抑制与无天冬酰胺培养基的联合使用导致细胞增殖减少。联合处理抑制了核苷酸合成并促进了细胞周期停滞。在体内，ETC抑制与PEG-Asnase的联合使用限制了肿瘤生长。结论：天冬酰胺富集和mTORC1上调是促进WD/DD LPS肿瘤进展的重要因素。有效的靶向策略需要限制细胞外天冬酰胺的获取并抑制其从头合成机制。PEG-Asnase与ETC抑制的联合使用是限制WD/DD LPS肿瘤生长的有效疗法。
Targeting Asparagine Metabolism in Well-Differentiated/Dedifferentiated Liposarcoma
肿瘤(癌症)患者之家