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Serine restriction alters sphingolipid diversity to constrain tumour growth

Author

Listed:
  • Thangaselvam Muthusamy

    (University of California San Diego)

  • Thekla Cordes

    (University of California San Diego)

  • Michal K. Handzlik

    (University of California San Diego)

  • Le You

    (University of California San Diego)

  • Esther W. Lim

    (University of California San Diego)

  • Jivani Gengatharan

    (University of California San Diego)

  • Antonio F. M. Pinto

    (Salk Institute for Biological Studies)

  • Mehmet G. Badur

    (University of California San Diego)

  • Matthew J. Kolar

    (Salk Institute for Biological Studies)

  • Martina Wallace

    (University of California San Diego)

  • Alan Saghatelian

    (Salk Institute for Biological Studies)

  • Christian M. Metallo

    (University of California San Diego
    University of California, San Diego)

Abstract

Serine, glycine and other nonessential amino acids are critical for tumour progression, and strategies to limit their availability are emerging as potential therapies for cancer1–3. However, the molecular mechanisms driving this response remain unclear and the effects on lipid metabolism are relatively unexplored. Serine palmitoyltransferase (SPT) catalyses the de novo biosynthesis of sphingolipids but also produces noncanonical 1-deoxysphingolipids when using alanine as a substrate4,5. Deoxysphingolipids accumulate in the context of mutations in SPTLC1 or SPTLC26,7—or in conditions of low serine availability8,9—to drive neuropathy, and deoxysphinganine has previously been investigated as an anti-cancer agent10. Here we exploit amino acid metabolism and the promiscuity of SPT to modulate the endogenous synthesis of toxic deoxysphingolipids and slow tumour progression. Anchorage-independent growth reprogrammes a metabolic network involving serine, alanine and pyruvate that drives the endogenous synthesis and accumulation of deoxysphingolipids. Targeting the mitochondrial pyruvate carrier promotes alanine oxidation to mitigate deoxysphingolipid synthesis and improve spheroid growth, similar to phenotypes observed with the direct inhibition of SPT or ceramide synthesis. Restriction of dietary serine and glycine potently induces the accumulation of deoxysphingolipids while decreasing tumour growth in xenograft models in mice. Pharmacological inhibition of SPT rescues xenograft growth in mice fed diets restricted in serine and glycine, and the reduction of circulating serine by inhibition of phosphoglycerate dehydrogenase (PHGDH) leads to the accumulation of deoxysphingolipids and mitigates tumour growth. The promiscuity of SPT therefore links serine and mitochondrial alanine metabolism to membrane lipid diversity, which further sensitizes tumours to metabolic stress.

Suggested Citation

  • Thangaselvam Muthusamy & Thekla Cordes & Michal K. Handzlik & Le You & Esther W. Lim & Jivani Gengatharan & Antonio F. M. Pinto & Mehmet G. Badur & Matthew J. Kolar & Martina Wallace & Alan Saghatelia, 2020. "Serine restriction alters sphingolipid diversity to constrain tumour growth," Nature, Nature, vol. 586(7831), pages 790-795, October.
  • Handle: RePEc:nat:nature:v:586:y:2020:i:7831:d:10.1038_s41586-020-2609-x
    DOI: 10.1038/s41586-020-2609-x
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    Citations

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    Cited by:

    1. Ziwei Dai & Weiyan Zheng & Jason W. Locasale, 2022. "Amino acid variability, tradeoffs and optimality in human diet," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Zidan Wang & Donghui Zhang & Junhan Wu & Wenpeng Zhang & Yu Xia, 2024. "Illuminating the dark space of neutral glycosphingolipidome by selective enrichment and profiling at multi-structural levels," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Philipp Hammerschmidt & Sophie M. Steculorum & Cécile L. Bandet & Almudena Río-Martín & Lukas Steuernagel & Vivien Kohlhaas & Marvin Feldmann & Luis Varela & Adam Majcher & Marta Quatorze Correia & Rh, 2023. "CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    5. Niranjan Venkateswaran & Roy Garcia & M. Carmen Lafita-Navarro & Yi-Heng Hao & Lizbeth Perez-Castro & Pedro A. S. Nogueira & Ashley Solmonson & Ilgen Mender & Jessica A. Kilgore & Shun Fang & Isabella, 2024. "Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Hanyu Rao & Changwei Liu & Aiting Wang & Chunxiao Ma & Yue Xu & Tianbao Ye & Wenqiong Su & Peijun Zhou & Wei-Qiang Gao & Li Li & Xianting Ding, 2023. "SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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