Neutrophils escort circulating tumour cells to enable cell cycle progression
Neutrophils escort circulating tumour cells to enable cell cycle progression
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DOI：
10.1038/s41586-019-0915-y
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发表时间：
2019-02-28
期刊：
影响因子：
64.8
通讯作者：
Aceto, Nicola
中科院分区：
文献类型：
--
作者：
Szczerba, Barbara Maria;Castro-Giner, Francesc;Aceto, Nicola
更好地了解癌细胞和免疫细胞之间相互作用的特征对于开发新的癌症治疗方法非常重要(1)。然而，重点往往是发生在原发肿瘤及其微环境内的相互作用，而免疫细胞在患者癌症传播过程中的作用在很大程度上仍未确定（2,3）。循环肿瘤细胞（CTCs）是几种类型癌症转移的前体（4-6），并且偶尔在血液中发现与非恶性细胞（如白细胞（wbc））相关（7,8）。这些与ctc相关的白细胞的身份和功能，以及定义wbc和ctc之间相互作用的分子特征，都是未知的。在这里，我们从乳腺癌患者和小鼠模型中分离并表征了单个ctc相关的白细胞，以及每个CTC-WBC簇中相应的癌细胞。我们使用单细胞RNA测序显示，在大多数情况下，ctc与中性粒细胞相关。当比较与中性粒细胞相关的CTCs与单独的CTCs的转录组谱时，我们发现了许多差异表达的基因，这些基因勾勒出细胞周期的进展，导致更有效的转移形成。此外，我们鉴定了细胞-细胞连接和细胞因子受体对，它们定义了ctc -中性粒细胞簇，代表了转移过程的关键脆弱性。因此，中性粒细胞和ctc之间的关联驱动了血液中的细胞周期进程，扩大了ctc的转移潜力，为靶向这种相互作用治疗乳腺癌提供了理论依据。
A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies(1). However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized(2,3). Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer(4-6), and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs)(7,8). The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC-WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell-cell junction and cytokine-receptor pairs that define CTC-neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer.