p53缺失驱动头颈癌神经元重编程
2020-02-14   阅读:599   来源:自然

美国德克萨斯大学MD安德森癌症中心Jeffrey N. Myers、George A. Calin、Moran Amit等研究人员合作发现,p53缺失驱动头颈癌中的神经元重编程。这一研究成果2020年2月12日在线发表于国际学术期刊《自然》。

通过比较口腔癌小鼠模型中与癌症相关的三叉神经感觉神经元和内源性神经元的转录组,研究人员确定了肾上腺能分化标志。他们发现,TP53的丢失通过小RNA miR-34a的丢失导致与肿瘤相关的感觉神经的肾上腺素能转分化。肾上腺素能受体的损伤或药理阻碍抑制了肿瘤的生长,但已经存在的肾上腺素能神经的化学交感神经切除术并未抑制肿瘤的生长。对口腔癌样品的回顾性分析显示,p53的状态与神经密度有关,而神经密度又与不良的临床结果有关。癌细胞与神经元之间的这种交流表明,肿瘤相关的神经元重新编程为形成促进肿瘤进展的肾上腺素能表型,并且这也是癌症治疗的潜在靶标。

据悉,实体瘤微环境包含来自周围神经系统的神经纤维。最近的工作表明,新形成的肾上腺素能神经纤维可以促进肿瘤的生长,但是这些神经的起源及其发生的机制尚不清楚。

附:英文原文

Title: Loss of p53 drives neuron reprogramming in head and neck cancer

Author: Moran Amit, Hideaki Takahashi, Mihnea Paul Dragomir, Antje Lindemann, Frederico O. Gleber-Netto, Curtis R. Pickering, Simone Anfossi, Abdullah A. Osman, Yu Cai, Rong Wang, Erik Knutsen, Masayoshi Shimizu, Cristina Ivan, Xiayu Rao, Jing Wang, Deborah A. Silverman, Samantha Tam, Mei Zhao, Carlos Caulin, Assaf Zinger, Ennio Tasciotti, Patrick M. Dougherty, Adel El-Naggar, George A. Calin, Jeffrey N. Myers

Issue&Volume: 2020-02-12

Abstract: The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system1,2. 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 unknown1,3. 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.

DOI: 10.1038/s41586-020-1996-3

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