乳腺癌单细胞转移之初的时空演化

肿瘤转移所引起的死亡仍是乳腺癌治疗中尚未解决的难题，而腋窝淋巴结是乳腺癌最常见也是最早期的转移部位。单细胞RNA测序和空间转录组测序作为肿瘤研究中的新兴技术，从单细胞水平对转移过程中的乳腺癌肿瘤细胞随着时空演进的行为进行更加详细解析。

2023年1月3日，德国《先进科学》在线发表复旦大学附属肿瘤医院刘燚铭、葛靖宇、陈雨霏、陈列、刘翠翠、马丁、陈一瑜、蔡毓文、邵志敏、余科达✉️、哈尔滨医科大学附属肿瘤医院刘通、中国医科大学附属第一医院徐莹莹等学者的研究报告，揭示了乳腺癌早期转移亚群在转移过程中氧化磷酸化通路和糖酵解通路活性的互相演变，并发现了该亚群在乳腺癌原发肿瘤的空间分布特征，提示了氧化磷酸化对于预测乳腺癌淋巴结转移的潜在价值。

该研究获得原发灶和配对的淋巴结转移灶之后，构建了包含6万5968个细胞的单细胞数据库，从中鉴定出同时出现在原发灶和淋巴转移灶的乳腺癌早期转移亚群。该亚群呈现出明显的氧化磷酸化活性上调特征，并且在转移过程中氧化磷酸化通路活性表现出先上升后下降的趋势，而糖酵解通路则出现相反的变化趋势，表明转移亚群的代谢模式在早期转移过程中存在明显的转化。

研究团队又通过对原发灶的单细胞RNA测序和空间转录组测序的联合分析，揭示了乳腺癌早期转移亚群主要分布于原发灶边界的空间分布特征，呈现出较高的氧化磷酸化通路和上皮-间质转化通路活性以及根据乳腺癌早期转移亚群特征定义的乳腺癌转移分数。

最后该研究团队通过实验验证了氧化磷酸化通路与乳腺癌细胞上皮-间质转化之间的相关性，并利用美国癌症基因组图谱（TCGA）、国际乳腺癌分子分类学联盟（METABRIC）以及外部乳腺癌单细胞数据库验证了氧化磷酸化通路与乳腺癌淋巴结转移的关系和潜在的预后价值。

在邵志敏教授的指导下，余科达教授领衔的团队近年来在国家自然科学基金委员会优秀青年基金等5项国家级项目、上海市教育委员会科研创新计划重大项目、上海市优秀学术带头人、上海市教育委员会曙光计划等项目资助下，聚焦乳腺癌各分子亚型进行深入的临床和基础转化研究，取得一系列创新成果。多项关键成果被美国国家综合癌症网络指南、美国临床肿瘤学会指南、德国妇科肿瘤协作组指南、中国抗癌协会乳腺癌诊治指南与规范等国际权威指南收录，改变了全球乳腺癌临床实践。论文以通信作者发表于JAMA Oncol、Nat Commun、Sci Adv、J Natl Cancer Inst、Lancet Reg Health West Pac等国际权威期刊，成果获全国妇幼健康科学技术成果一等奖、中国抗癌协会科技一等奖、上海市科技进步一等奖、上海市抗癌科技一等奖等。余科达教授担任香港研究资助局、澳门科学技术发展基金、教育部学位与研究生教育发展中心、国家自然科学基金委员会等评审专家，也是全球早期乳腺癌试验者协作组（EBCTCG）指导委员会委员。

Adv Sci (Weinh). 2023 Jan 3. IF: 17.521 Combined Single-Cell and Spatial Transcriptomics Reveal the Metabolic Evolvement of Breast Cancer during Early Dissemination. Liu YM, Ge JY, Chen YF, Liu T, Chen L, Liu CC, Ma D, Chen YY, Cai YW, Xu YY, Shao ZM, Yu KD✉️. Shanghai Cancer Center and Cancer Institute, Fudan University, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China; The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. By single-cell RNA sequencing and spatial transcriptomics, the early early-disseminated breast cancer cells are found to travel from the border of primary tumor to axillary lymph nodes. During this metastasis, a switch between glycolysis and oxidative phosphorylation occurs in early disseminated breast cancer cells, indicating an interesting dynamic metabolic evolvement . Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA-seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis. PMID : 36594618 DOI : 10.1002/advs.202205395 - END -

来源：SIBCS

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