Serine restriction alters sphingolipid diversity to constrain tumour growth

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 Saghatelian and Christian M. Metallo ()
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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

Nature, 2020, vol. 586, issue 7831, 790-795

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2609-x

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