张贝 (2022-06-30 23:44):
#paper DOI: 10.1038/s41556-020-0477-0 Nat Cell Biol. 2020 Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. 本文建立了患者来源的乳腺癌异种移植(PDX)小鼠模型,利用单细胞测序技术来检测乳腺癌转移过程中少量转移细胞的转录组变化。通路分析显示线粒体氧化磷酸化是微转移肿瘤上调的top通路,而乳腺癌原发灶主要是糖酵解酶上调。利用流式细胞分析,qPCR以及代谢组学证明微转移灶中氧化磷酸化途径的上调。当使用寡霉素抑制氧化磷酸化途径时,可显著减弱乳腺癌肿瘤转移至肺,表明线粒体氧化磷酸化途径可作为防止乳腺癌患者转移的治疗靶点。本研究表明,转移的乳腺癌细胞不是通过糖酵解来获得能量,而是优先通过线粒体氧化磷酸化途径供能,这为预防癌症的扩散提供了新思路。
IF:17.300Q1 Nature cell biology, 2020-03. DOI: 10.1038/s41556-020-0477-0 PMID: 32144411
Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing
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Abstract:
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.
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