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Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis within the PDAC Tumor
Anna S Trimble1,2, Casie S Kubota2,3, Elaine Zhao2,4
1Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy where metabolic homeostasis is maintained by tumor and stromal cells within the tumor microenvironment (TME). To better assess pathways supporting macromolecule biosynthesis in PDAC tumors, we apply 13C metabolic flux analysis (MFA) to slice cultures of treatment-naïve human tumors and mouse models that retain the native TME. Glycans, lipid headgroups, and very long-chain fatty acids are the most dynamic metabolic pools, while long chain fatty acids, purines, and pyrimidines are predominantly salvaged locally in situ. We use targeted pharmacological modulators to highlight the importance of recycling pathways and metabolic redundancies which mitigate changes in lipid abundances. Finally, we leverage targeted lipid fluxomics and the distinct ganglioside and globoside profiles of tumor and stromal cells, respectively, to demonstrate the role of the lipid kinase PIKfyve in supporting ganglioside homeostasis via sialic acid and ceramide salvage. These data establish application of MFA to slice cultures of PDAC tumors as an effective approach for assessing metabolic mechanisms and therapeutic responses within an intact TME.
Insights
Pancreatic cancer cells maintain metabolic balance using tumor microenvironment interactions. Researchers used 13C metabolic flux analysis (MFA) in intact tumors to reveal key metabolic pathways and identify PIKfyve as crucial for lipid homeostasis.
Area of Science:
- Oncology
- Metabolomics
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer.
- Metabolic homeostasis in PDAC relies on tumor and stromal cell interactions within the tumor microenvironment (TME).
- Understanding macromolecule biosynthesis pathways is crucial for PDAC treatment strategies.
Purpose of the Study:
- To assess macromolecule biosynthesis pathways in PDAC tumors.
- To investigate metabolic mechanisms and therapeutic responses within the intact TME.
- To identify key metabolic vulnerabilities and salvage pathways in PDAC.
Main Methods:
- Applied 13C metabolic flux analysis (MFA) to slice cultures of treatment-naïve human PDAC tumors and mouse models.
- Utilized targeted pharmacological modulators to study metabolic recycling and redundancies.
- Employed targeted lipid fluxomics and analyzed distinct ganglioside and globoside profiles.
Main Results:
- Glycans, lipid headgroups, and very long-chain fatty acids were the most dynamic metabolic pools.
- Long chain fatty acids, purines, and pyrimidines were predominantly salvaged locally.
- PIKfyve was identified to support ganglioside homeostasis through sialic acid and ceramide salvage.
Conclusions:
- MFA on PDAC tumor slice cultures is effective for studying metabolism within an intact TME.
- Recycling pathways and metabolic redundancies play significant roles in mitigating lipid abundance changes.
- Targeting PIKfyve may offer a therapeutic strategy for PDAC by disrupting ganglioside homeostasis.
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