Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness.
Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness.
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DOI：
10.1038/s41392-023-01487-4
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发表时间：
2023-07-19
影响因子：
39.3
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
--
作者：
He, Bin;Gao, Rui;Lv, Shasha;Chen, Ailin;Huang, Junxiu;Wang, Luoxuan;Feng, Yunxiu;Feng, Jiesi;Liu, Bing;Lei, Jie;Deng, Bing;He, Bin;Cui, Bai;Peng, Fei;Yan, Min;Wang, Zifeng;Lam, Eric W-F;Jin, Bilian;Shao, Zhiming;Li, Yulong;Jiao, Jianwei;Wang, Xi;Liu, Quentin
癌细胞接受细胞外信号输入以获得干细胞样状态，然而肿瘤微环境(TME)神经信号如何引导肿瘤干细胞建立分层的肿瘤结构仍然难以捉摸。在这里，对33种TCGA癌类型的10852个样本的泛癌转录筛选显示，cAMP反应元件(Cre)转录因子是癌症干性的汇聚激活剂。转录图谱的反卷积、神经标记物的规范和去甲肾上腺素动力学的图解揭示了TME神经信号和癌细胞Cre活性之间的联系。具体地说，神经信号去甲肾上腺素通过激活cAMP-Cre轴来增强近端癌细胞的干性，在cAMP-Cre轴中，atf1充当保守的枢纽。在被去甲肾上腺素激活后，atf1通过协调激活核多能因子MYC/NANOG和线粒体生物发生调节因子NRF1/TFAM来增强癌症的干性，从而协调核重新编程和线粒体恢复活力。因此，单细胞转录本证实了癌症干细胞中核多能性与线粒体生物发生的协调激活。这些发现阐明了癌细胞通过去甲肾上腺素-atf1驱动的核-线粒体协作程序获得茎，这表明通过劫持微环境神经信号获得了空间化的茎。
Cancer cell receives extracellular signal inputs to obtain a stem-like status, yet how tumor microenvironmental (TME) neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive. Here, a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element (CRE) transcription factors are convergent activators for cancer stemness. Deconvolution of transcriptomic profiles, specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity. Specifically, neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis, where ATF1 serves as a conserved hub. Upon activation by norepinephrine, ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM, thereby orchestrating nuclear reprograming and mitochondrial rejuvenating. Accordingly, single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells. These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program, suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.2
作者：
Carriba, Paulina;Pardo, Luis;Galea, Elena
通讯作者：
Galea, Elena
影响因子：
16.6
作者：
Cho MH;Park JH;Choi HJ;Park MK;Won HY;Park YJ;Lee CH;Oh SH;Song YS;Kim HS;Oh YH;Lee JY;Kong G
通讯作者：
Kong G
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK