Targeting Asparagine Metabolism in Well-Differentiated/Dedifferentiated Liposarcoma

Kyle D Klingbeil; Blake R Wilde; Danielle S Graham; Serena Lofftus; Tyler McCaw; Nedas Matulionis; Sarah M Dry; Joseph G Crompton; Fritz C Eilber; Thomas G Graeber; David B Shackelford; Heather R Christofk; Brian E Kadera

doi:10.3390/cancers16173031

Targeting Asparagine Metabolism in Well-Differentiated/Dedifferentiated Liposarcoma

Cancers (Basel). 2024 Aug 30;16(17):3031. doi: 10.3390/cancers16173031.

Authors

Kyle D Klingbeil^{1

2}, Blake R Wilde^{2

3

4}, Danielle S Graham^{1

2}, Serena Lofftus^{1

2}, Tyler McCaw^{1

2}, Nedas Matulionis^{3

4}, Sarah M Dry^{2

5}, Joseph G Crompton^{1

2}, Fritz C Eilber^{1

2}, Thomas G Graeber^{2

6}, David B Shackelford^{2

7}, Heather R Christofk^{2

3

4}, Brian E Kadera^{1

2}

Affiliations

¹ Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, 10833 Le Conte Ave, 54-117, Los Angeles, CA 90095, USA.
² Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Pathology, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Medicine, Division of Pulmonology and Critical Care, University of California Los Angeles, Los Angeles, CA 90095, USA.

Abstract

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.

Keywords: ATF4; asparaginase; asparagine metabolism; complex I inhibitor; electron transport chain; mTORC1 signaling; patient-derived organoids; patient-derived xenograft; well-differentiated/dedifferentiated liposarcoma.

Abstract

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