Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets
Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets
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基于代谢途径的三阴性乳腺癌亚型揭示了潜在的治疗靶点
DOI：
10.1016/j.cmet.2020.10.012
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发表时间：
2021-01-05
期刊：
影响因子：
29
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
--
作者：
Gong, Yue;Ji, Peng;Shao, Zhi-Ming
三阴性乳腺癌（TNBC）仍然是一个尚未解决的医学挑战。我们通过使用我们的多组学数据库（n = 465，迄今为止最大的）研究了TNBC的代谢失调。将TNBC样品分为具有不同代谢特征的三种基于异质代谢途径的亚型（MPS）：MPS 1，具有上调的脂质代谢的脂肪生成亚型; MPS 2，具有上调的碳水化合物和核苷酸代谢的糖酵解亚型;和MPS 3，具有部分途径失调的混合亚型。这些亚型通过72个样品的代谢组学分析进行了验证。这三种亚型具有不同的遗传多样性、分子亚型分布和基因组改变。此外，MPS 1 TNBC对靶向脂肪酸合成的代谢抑制剂更敏感，而MPS 2 TNBC对靶向糖酵解的抑制剂显示出更高的敏感性。重要的是，乳酸脱氢酶的抑制可以增强MPS 2 TNBC中对抗PD-1免疫疗法的肿瘤应答。总的来说，我们的分析证明了TNBC的代谢异质性，并能够开发针对独特肿瘤代谢特征的个性化治疗。
Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of iactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.