编辑精选：探索三阴性乳腺癌代谢弱点
三阴性乳腺癌是不表达雌激素受体或孕激素受体且不过表达人类表皮生长因子受体HER2的乳腺癌亚型。在所有乳腺癌亚型中，其预后最差且治疗选择有限。代谢靶向疗法是三阴性乳腺癌的诱人策略；不过，三阴性乳腺癌的代谢特征各不相同，并无共同的代谢靶点。2020年11月11日，美国《细胞》旗下《细胞代谢》在线发表复旦大学附属肿瘤医院龚悦等学者的研究报告，探讨了三阴性乳腺癌的代谢差异性，以促进代谢靶向疗法的针对性。
2020年11月25日，美国科学促进会《科学》旗下《转化医学》编辑精选栏目在线发表纽约西奈山医院附属伊坎医学院帝势癌症研究所加拉格尔实验室主任艾米丽·加拉格尔教授的编辑精选：三阴性乳腺癌代谢弱点，对龚悦等学者的研究报告进行了点评。
该研究对465例三阴性乳腺癌女性的基因核糖核酸（RNA）进行转录组学分析，确定了三阴性乳腺癌的三种代谢途径亚型：
第一种亚型（MPS1）特征为脂质合成基因转录水平上调，代谢组学分析表明脂肪酸水平升高，磷脂酰肌醇双磷酸激酶催化亚基PIK3CA和磷酸酶张力蛋白同源物PTEN编码突变发生率高于其他代谢亚型。
第二种亚型（MPS2）特征为葡萄糖和核苷酸代谢基因转录水平上调，代谢组学分析表明葡萄糖水平降低、糖酵解和核苷酸代谢水平升高。
第三种亚型（MPS3）特征不太明确，具有混合的代谢基因表达特征。
这些代谢亚型的临床特征分析表明，MPS2与其他亚型相比，肿瘤分级显著较、无复发生存显著较差，还具有抗肿瘤免疫监视减弱的基因特征。
随后，该研究利用同基因肿瘤模型，分析糖酵解代谢靶向疗法能否影响程序性细胞死亡蛋白PD-1抑制剂的体内免疫疗效。结果发现，乳酸脱氢酶抑制剂可改善PD-1抑制剂的疗效，并增强MPS2（而非MPS1或MPS3）肿瘤小鼠的抗肿瘤免疫疗效。
因此，该研究揭示了三阴性乳腺癌的代谢差异性，以及理解该差异性对于药物治疗研究的重要性，三阴性乳腺癌的代谢特征分析可能促进个体化治疗。不过，该研究尚未进一步分析全身代谢状况是否影响三阴性乳腺癌的代谢亚型或代谢靶向治疗效果。考虑到代谢综合征与三阴性乳腺癌之间的关联，以及肥胖与癌症免疫治疗效果之间的关联，这些问题将至关重要。
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Sci Transl Med. 2020 Nov 25;12(571):eabf7102.
The metabolic foibles of triple negative breast cancer.
Emily J. Gallagher
Gallagher Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Metabolic profiling of triple-negative breast cancers may advance personalized therapies.
Triple-negative breast cancer (TNBC) is the subtype of breast cancer that does not express the estrogen receptor or progesterone receptor and does not overexpress human epidermal growth factor 2. Of all breast cancer subtypes, it carries the worst prognosis and has limited treatment options. Metabolism-targeting therapeutics are an attractive strategy for TNBC; however, TNBC is a heterogeneous disease. Gong and colleagues aimed to understand the metabolic heterogeneity within TNBC to improve specificity of metabolism-targeting therapies.
Through transcriptomic profiling of breast cancers from a cohort of women, the authors identified three metabolic pathway-based subtypes (MPSs) of TNBC. The first subtype, called MPS1, was characterized by up-regulation of lipid synthesis genes, a greater abundance of fatty acids on metabolomic analysis, and a higher prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and phosphatase and tensin homolog (PTEN) mutations than other metabolic subtypes. The second subtype (MPS2) demonstrated up-regulation of glucose and nucleotide metabolism genes, along with decreased glucose abundance and increased concentrations of intermediates of glycolysis and nucleotide metabolism. The third subtype (MPS3) was less well-defined, with mixed metabolic gene expression characteristics. Examining the clinical features of these metabolic subtypes revealed that MPS2 was associated with higher tumor grade and worse relapse-free survival than the other subtypes. They also found that the MPS2 subtype had a gene signature consistent with decreased anti-tumor immune surveillance.
Gong and colleagues next examined whether therapeutically targeting glycolytic metabolism would affect response to anti-programmed cell death protein 1 (PD-1) immunotherapy in vivo, using syngeneic tumor models. They found that inhibiting lactate dehydrogenase improved response to anti-PD-1 therapy and increased the anti-tumor immune response in mice carrying MPS2 tumors but not MPS1 or MPS3 tumors.
These studies reveal the metabolic heterogeneity of TNBC and the importance of understanding this heterogeneity in therapeutic studies. The authors did not examine whether systemic metabolic conditions affected the TNBC metabolic subtype or the response to metabolism-targeting therapies. These questions will be important given the association between metabolic syndrome and TNBC and the links between obesity and response to cancer immunotherapy.
DOI: 10.1126/scitranslmed.abf7102