Serine, glycine and other nonessential amino acids are critical for tumour progression, and strategies to limit their availability are emerging as potential therapies for cancer 1 – 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 substrate 4 , 5 . Deoxysphingolipids accumulate in the context of mutations in SPTLC1 or SPTLC2 6 , 7 —or in conditions of low serine availability 8 , 9 —to drive neuropathy, and deoxysphinganine has previously been investigated as an anti-cancer agent 10 . 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. In xenograft tumour models in mice, modulation of dietary serine, serine palmitoyltransferase or phosphoglycerate dehydrogenase activity enables control of the endogenous synthesis of deoxysphingolipids, sensitizing the tumours to metabolic stress and slowing their progression.

中文翻译：

---

丝氨酸限制改变鞘脂多样性以限制肿瘤生长

丝氨酸、甘氨酸和其他非必需氨基酸对肿瘤进展至关重要，限制其可用性的策略正在成为癌症的潜在疗法 1-3 。然而，驱动这种反应的分子机制仍不清楚，对脂质代谢的影响也相对未探索。丝氨酸棕榈酰转移酶 (SPT) 催化鞘脂的从头生物合成，但在使用丙氨酸作为底物 4、5 时也会产生非常规的 1-脱氧鞘脂。脱氧鞘脂在 SPTLC1 或 SPTLC2 6, 7 突变的背景下 - 或在丝氨酸可用性低的条件下 8, 9 - 积累以驱动神经病变，而脱氧鞘氨醇先前已被研究为抗癌剂 10。在这里，我们利用氨基酸代谢和 SPT 的混杂性来调节有毒脱氧鞘脂的内源性合成并减缓肿瘤进展。不依赖锚定的生长重新编程涉及丝氨酸、丙氨酸和丙酮酸的代谢网络，驱动内源性合成和脱氧鞘脂的积累。靶向线粒体丙酮酸载体促进丙氨酸氧化以减轻脱氧鞘脂合成并改善球体生长，类似于直接抑制 SPT 或神经酰胺合成观察到的表型。限制饮食中的丝氨酸和甘氨酸可有效诱导脱氧鞘脂的积累，同时降低小鼠异种移植模型中的肿瘤生长。SPT 的药理抑制可挽救限制丝氨酸和甘氨酸饮食的小鼠的异种移植物生长，通过抑制磷酸甘油酸脱氢酶 (PHGDH) 减少循环丝氨酸会导致脱氧鞘脂的积累并减缓肿瘤生长。因此，SPT 的杂乱性将丝氨酸和线粒体丙氨酸代谢与膜脂多样性联系起来，这进一步使肿瘤对代谢应激敏感。在小鼠异种移植肿瘤模型中，调节膳食丝氨酸、丝氨酸棕榈酰转移酶或磷酸甘油酸脱氢酶活性能够控制脱氧鞘脂的内源性合成，使肿瘤对代谢应激敏感并减缓其进展。因此，SPT 的杂乱性将丝氨酸和线粒体丙氨酸代谢与膜脂多样性联系起来，这进一步使肿瘤对代谢应激敏感。在小鼠异种移植肿瘤模型中，调节膳食丝氨酸、丝氨酸棕榈酰转移酶或磷酸甘油酸脱氢酶活性能够控制脱氧鞘脂的内源性合成，使肿瘤对代谢应激敏感并减缓其进展。因此，SPT 的杂乱性将丝氨酸和线粒体丙氨酸代谢与膜脂多样性联系起来，这进一步使肿瘤对代谢应激敏感。在小鼠异种移植肿瘤模型中，调节膳食丝氨酸、丝氨酸棕榈酰转移酶或磷酸甘油酸脱氢酶活性能够控制脱氧鞘脂的内源性合成，使肿瘤对代谢应激敏感并减缓其进展。