Head and neck cancer exosomes drive microRNA-mediated reprogramming of local neurons.

Patrick J Hunt, Moran Amit
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Abstract

Solid tumors are complex collections of cells surrounded by benign tissues that influence and are influenced by the tumor. These surrounding cells include vasculature, immune cells, neurons, and other cell types, and are collectively known as the tumor microenvironment. Tumors manipulate their microenvironment for the benefit of the tumor. Autonomic neurons innervate and drive malignant growth in a variety of solid tumors. However, the mechanisms underlying neuron-tumor relationships are not well understood. Recently, Amit et al. described that trophic relationships between oral cavity squamous cell carcinomas (OCSCCs) and nearby autonomic neurons arise through direct signaling between tumors and local neurons. An inducible tumor model in which 4NQO was introduced into the drinking water of Trp53 knockout mice was used to model OCSCC-microenvironment interactions. Using this model, this group discovered that loss of p53 expression in OCSCC tumors resulted in increased nerve density within these tumors. This neuritogenesis was controlled by tumor-derived microRNA-laden extracellular vesicles (EVs). Specifically, EV-delivered miR-34a inhibited neuritogenesis, whereas EV-delivered miR-21 and miR-324 increased neuritogenesis. The neurons innervating p53-deficient OCSCC tumors were predominantly adrenergic and arose through the transdifferentiation of trigeminal sensory nerve fibers to adrenergic nerve fibers. This transdifferentiation corresponded with increased expression of neuron-reprogramming transcription factors, including POU5F1, KLF4, and ASCL1, which were overexpressed in the p53-deficient samples, and are proposed targets of miR-34a-mediated regulation. Human OCSCC samples enriched in adrenergic neuron markers are associated strongly with poor outcomes, thus demonstrating the relevance of these findings to cancer patients.

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头颈部癌症外泌体驱动微RNA介导的局部神经元重编程
实体瘤是由细胞组成的复杂集合体,周围有影响肿瘤和受肿瘤影响的良性组织。这些周围细胞包括血管、免疫细胞、神经元和其他细胞类型,统称为肿瘤微环境。肿瘤会操纵其微环境,使肿瘤受益。自主神经支配并驱动多种实体瘤的恶性生长。然而,神经元与肿瘤关系的内在机制并不十分清楚。最近,Amit 等人描述了口腔鳞状细胞癌(OCSCC)和附近自主神经元之间的营养关系是通过肿瘤和局部神经元之间的直接信号传导产生的。研究人员利用一种诱导性肿瘤模型,即在 Trp53 基因敲除小鼠的饮用水中引入 4NQO 来模拟 OCSCC 与微环境之间的相互作用。利用这一模型,该研究小组发现,OCSCC 肿瘤中 p53 表达缺失会导致肿瘤内神经密度增加。这种神经发生受肿瘤衍生的microRNA载体细胞外囊泡(EVs)控制。具体来说,EV递送的miR-34a抑制了神经发生,而EV递送的miR-21和miR-324则增加了神经发生。支配p53缺陷型OCSCC肿瘤的神经元主要是肾上腺素能神经元,是通过三叉神经感觉神经纤维向肾上腺素能神经纤维的转分化而产生的。这种转分化与神经元重编程转录因子(包括 POU5F1、KLF4 和 ASCL1)的表达增加相对应,这些转录因子在 p53 缺失的样本中表达过高,被认为是 miR-34a 介导的调控靶标。富含肾上腺素能神经元标记物的人类 OCSCC 样本与不良预后密切相关,因此这些发现与癌症患者息息相关。
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