Loss of p53 drives neuron reprogramming in head and neck cancer.
Loss of p53 drives neuron reprogramming in head and neck cancer.
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作者：
实体瘤微环境包括来自外周神经系统的神经纤维。最近的研究表明，新形成的肾上腺素能神经纤维促进肿瘤生长，但这些神经的起源和其发病机制尚不清楚。在这里，通过比较肿瘤相关三叉神经感觉神经元的转录组与口腔癌小鼠模型中内源性神经元的转录组，我们确定了肾上腺素能分化特征。我们发现TP 53的缺失通过microRNA miR-34 a的缺失导致肿瘤相关感觉神经的肾上腺素能转分化。感觉去神经支配或肾上腺素能受体的药物阻断抑制肿瘤生长，但不通过化学交感神经切除术预先存在的肾上腺素能神经。对口腔癌样本的回顾性分析显示，p53状态与神经密度相关，而神经密度又与不良临床结局相关。癌细胞和神经元之间的这种串扰代表了肿瘤相关神经元被重编程为肾上腺素能表型的机制，该肾上腺素能表型可以刺激肿瘤进展，并且是抗癌治疗的潜在靶标。
The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.
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影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1126/science.aag1927
发表时间：
2017-02-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choi YJ;Lin CP;Risso D;Chen S;Kim TA;Tan MH;Li JB;Wu Y;Chen C;Xuan Z;Macfarlan T;Peng W;Lloyd KC;Kim SY;Speed TP;He L
通讯作者：
He L
影响因子：
15.9
作者：
ANTONIADES, HN;GALANOPOULOS, T;LYNCH, SE
通讯作者：
LYNCH, SE
影响因子：
64.5
作者：
Lewis, BP;Shih, IH;Burge, CB
通讯作者：
Burge, CB