Serine restriction alters sphingolipid diversity to constrain tumor growth

Serine, glycine, and other non-essential amino acids are critical for tumor progression, and strategies to limit their availability are emerging as potential cancer therapies(1–3). However, the molecular mechanisms driving this response remain unclear, and the impact on lipid metabolism is relatively unexplored. Serine palmitoyltransferase (SPT) catalyzes the de novo biosynthesis of sphingolipids but also produces non-canonical 1-deoxysphingolipids (doxSLs) when using alanine as a substrate(4,5). DoxSLs accumulate in the context of SPTLC1 or SPTLC2 mutations(6,7) or low serine availability(8,9) to drive neuropathy, and deoxysphinganine (doxSA) has been investigated as an anti-cancer agent(10). Here we exploit amino acid metabolism and SPT promiscuity to modulate the endogenous synthesis of toxic doxSLs and slow tumor progression. Anchorage-independent growth reprograms a metabolic network involving serine, alanine, and pyruvate resulting in increased susceptibility to endogenous doxSL synthesis. Targeting the mitochondrial pyruvate carrier (MPC) promotes alanine oxidation to mitigate doxSL synthesis and improves spheroid growth, while direct inhibition of doxSL synthesis drives similar phenotypes. Restriction of dietary serine/glycine potently induces accumulation of doxSLs in xenografts while decreasing tumor growth. Pharmacological modulation of SPT rescues xenograft growth on serine/glycine-restricted diets, while reduction of circulating serine by inhibition of phosphoglycerate dehydrogenase (PHGDH) leads to doxSL accumulation and mitigates tumor growth. SPT promiscuity therefore links serine and mitochondrial alanine metabolism to membrane lipid diversity, which sensitizes tumors to metabolic stress.