乳腺癌转移的单细胞分析揭示了与不良预后相关的上皮-间质可塑性特征。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-09-03 DOI:10.1172/JCI164227
Juliane Winkler, Weilun Tan, Catherine Mm Diadhiou, Christopher S McGinnis, Aamna Abbasi, Saad Hasnain, Sophia Durney, Elena Atamaniuc, Daphne Superville, Leena Awni, Joyce V Lee, Johanna H Hinrichs, Patrick S Wagner, Namrata Singh, Marco Y Hein, Michael Borja, Angela M Detweiler, Su-Yang Liu, Ankitha Nanjaraj, Vaishnavi Sitarama, Hope S Rugo, Norma Neff, Zev J Gartner, Angela Oliveira Pisco, Andrei Goga, Spyros Darmanis, Zena Werb
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引用次数: 0

摘要

转移是癌症相关死亡的主要原因。目前还不清楚肿瘤内异质性(ITH)如何导致转移,以及转移细胞如何适应远处的组织环境。对这些适应性的研究面临挑战,因为获取患者材料的途径有限,而且缺乏能适当再现 ITH 的实验模型。为了研究转移细胞的适应性和 ITH 对转移的贡献,我们分析了匹配的原发肿瘤和乳腺癌患者异种移植模型转移灶的单细胞转录组。我们发现原发肿瘤和转移细胞之间存在着深刻的转录差异。原发肿瘤上调了多个代谢基因,而微转移瘤中上调了运动通路基因,并且在进展过程中上调了应激反应信号转导。此外,我们还发现了与转移潜力增加相关的原发肿瘤基因特征,这些特征与患者的预后相关。免疫调节控制通路在转移性较差的原发性肿瘤中富集,而参与上皮-间质转化的基因在高度转移性肿瘤中上调。我们发现,上皮-间质可塑性(EMP)在 ITH 中占主导地位,它呈现为一个动态连续体,中间的 EMP 细胞状态以 CRYAB 和 S100A2 等特定基因为特征。中间EMP特征表达的升高与患者预后的恶化相关。我们的研究发现,抑制中间EMP细胞状态是阻止转移的潜在治疗靶点。
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Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes.

Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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