Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy.
Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy.
复制标题
DOI：
10.1038/s41388-021-02174-w
复制
发表时间：
2022-03
期刊：
影响因子：
8
通讯作者：
Fatatis A
中科院分区：
文献类型：
--
作者：
DiNatale A;Kaur R;Qian C;Zhang J;Marchioli M;Ipe D;Castelli M;McNair CM;Kumar G;Meucci O;Fatatis A
转移起始细胞（Metastasis-initiating cells，MIC）具有干细胞样特征，可引起转移复发，抵抗化疗，最终导致患者死亡。在这里，我们发现前列腺癌和乳腺癌患者具有CX 3CR 1，OCT 4a（POU 5 F1）和NANOG高表达的肿瘤细胞。CX 3CR 1表达或信号传导受损阻碍了细胞系肿瘤球体的形成，我们从这些细胞系中分离出共表达CX 3CR 1和干细胞相关标志物的小亚群，与患者的肿瘤相似。这些罕见的CX 3CR 1High细胞显示出富含调节多能性的途径的转录组学特征，并在小鼠模型中具有转移起始行为。缺乏这些特征的癌细胞（CX 3CR 1低）能够随着时间的推移重新获得CX 3CR 1相关特征，这意味着MIC可以从非干细胞癌细胞中持续出现。CX 3CR 1表达也赋予多西他赛耐药性，多西他赛长期治疗选择了CX 3CR 1High表型，其具有凋亡途径的去富集转录组学特征。这些发现提名CX 3CR 1作为干细胞样肿瘤细胞的新标志物，并为将来开发靶向CX 3CR 1信号传导和（再）表达的方法作为预防或遏制转移起始的治疗手段提供了概念基础。
Metastasis-initiating cells (MICs) display stem cell-like features, cause metastatic recurrences and defy chemotherapy, which leads to patients’ demise. Here we show that prostate and breast cancer patients harbor contingents of tumor cells with high expression of CX3CR1, OCT4a (POU5F1) and NANOG. Impairing CX3CR1 expression or signaling hampered the formation of tumor spheroids by cell lines from which we isolated small subsets co-expressing CX3CR1 and stemness-related markers, similarly to patients’ tumors. These rare CX3CR1High cells show transcriptomic profiles enriched in pathways that regulate pluripotency and are endowed with metastasis-initiating behavior in murine models. Cancer cells lacking these features (CX3CR1Low) were capable of re-acquiring CX3CR1-associated features over time, implying that MICs can continuously emerge from non-stem cancer cells. CX3CR1 expression also conferred resistance to docetaxel, and prolonged treatment with docetaxel selected CX3CR1High phenotypes with de-enriched transcriptomic profiles for apoptotic pathways. These findings nominate CX3CR1 as novel marker of stem-like tumor cells and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation.
登录
查看更多内容
影响因子：
21.3
作者：
Er EE;Valiente M;Ganesh K;Zou Y;Agrawal S;Hu J;Griscom B;Rosenblum M;Boire A;Brogi E;Giancotti FG;Schachner M;Malladi S;Massagué J
通讯作者：
Massagué J
影响因子：
--
作者：
Bendas G;Borsig L
通讯作者：
Borsig L
影响因子：
5.2
作者：
Gassenmaier, Maximilian;Chen, Dong;Pohla, Heike
通讯作者：
Pohla, Heike
影响因子：
4
作者：
Dillekas, Hanna;Rogers, Michael S.;Straume, Oddhjorn
通讯作者：
Straume, Oddhjorn
DOI：
10.1038/nrm3591
发表时间：
2013-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--