Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing
Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing
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DOI：
10.1038/s41556-020-0477-0
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发表时间：
2020-03-01
影响因子：
21.3
通讯作者：
Lawson, Devon A.
中科院分区：
文献类型：
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作者：
Davis, Ryan T.;Blake, Kerrigan;Lawson, Devon A.
Davis等证明了乳腺癌微转移中与线粒体氧化磷酸化上调相关的异质性和独特的转录组程序。尽管转移仍然是大多数癌症相关死亡的原因，但对远端组织中控制播种的机制知之甚少。在这里，我们建立了一个强大的方法，用于识别全球转录组的变化，罕见的转移细胞在接种过程中使用单细胞RNA测序和患者来源的异种移植模型的乳腺癌。我们发现，原发性肿瘤和微转移瘤都显示出转录异质性，但微转移瘤具有一个独特的转录组程序，该程序在患者来源的异种移植模型中保守，高度预测患者的生存率。通路分析显示，线粒体氧化磷酸化作为微转移中上调的顶级通路，与原发性肿瘤细胞中较高水平的糖酵解酶相反，我们通过流式细胞术和代谢组学分析证实了这一点。氧化磷酸化的药理学抑制显著减弱了肺中的转移性种植，这证明了氧化磷酸化在转移中的功能重要性，并突出了其作为预防乳腺癌患者转移性扩散的治疗靶点的潜力。
Davis et al. demonstrate heterogeneous and distinct transcriptome programs in breast cancer micrometastasis associated with upregulated mitochondrial oxidative phosphorylation.Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer.