Epithelial-to-Mesenchymal Transition-Derived Heterogeneity in Head and Neck Squamous Cell Carcinomas.
Epithelial-to-Mesenchymal Transition-Derived Heterogeneity in Head and Neck Squamous Cell Carcinomas.
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DOI：
10.3390/cancers13215355
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发表时间：
2021-10-26
期刊：
影响因子：
5.2
通讯作者：
Gires O
中科院分区：
文献类型：
--
作者：
Baumeister P;Zhou J;Canis M;Gires O
头颈部鳞状细胞癌（HNSCC）是一种常见的恶性肿瘤，发病率高，死亡率高。对由手术、放疗、化疗和免疫治疗组成的多模式治疗方式的抵抗是HNSCC患者有效治疗的主要障碍。患者在诊断时经常显示淋巴结转移，并忍受早期复发，通常以局部复发的形式。分化程序，如上皮间质转化（EMT）允许个体肿瘤细胞采用细胞功能，这些功能是转移和治疗抗性发展的核心。在本综述文章中，EMT的分子基础和调控及其对HNSCC进展的影响将得到解决。头颈部鳞状细胞癌（HNSCC）是一种常见的肿瘤，其总体预后较差。生存率低是由于对多模式治疗的反应有限，转移和局部复发的发生率高。治疗包括手术、放疗（化疗）和EGFR特异性靶向治疗和免疫检查点抑制。使用多OMIC方法改善了对HNSCC不良结局的分子基础的理解，该方法揭示了DNA突变、转录组和（磷酸化）蛋白质组水平上的高度肿瘤间和肿瘤内异质性（ITH）。单细胞RNA测序（scRNA-seq）鉴定了与细胞周期、细胞应激、缺氧、上皮分化和部分上皮向间充质转化（pEMT）相关的RNA表达特征。后一个特征与淋巴结受累和不良临床特征相关。从机制上讲，向间充质表型的转变使肿瘤细胞具有迁移和侵袭能力，并对标准治疗具有增强的抗性。因此，在HNSCC中观察到的EMT的逐渐变化代表了肿瘤进展的有力驱动力，可以开辟新的途径来改善患者的分层和创新方法来打破治疗耐药性。这些方面的分子异质性将在本审查中进行讨论。
Head and neck squamous cell carcinomas (HNSCC) are common malignancies with considerable morbidity and a high death toll worldwide. Resistance towards multi-modal therapy modalities composed of surgery, irradiation, chemo- and immunotherapy represents a major obstacle in the efficient treatment of HNSCC patients. Patients frequently show nodal metastases at the time of diagnosis and endure early relapses, oftentimes in the form of local recurrences. Differentiation programs such as the epithelial-to-mesenchymal transition (EMT) allow individual tumor cells to adopt cellular functions that are central to the development of metastases and treatment resistance. In the present review article, the molecular basis and regulation of EMT and its impact on the progression of HNSCC will be addressed. Head and neck squamous cell carcinomas (HNSCC) are common tumors with a poor overall prognosis. Poor survival is resulting from limited response to multi-modal therapy, high incidence of metastasis, and local recurrence. Treatment includes surgery, radio(chemo)therapy, and targeted therapy specific for EGFR and immune checkpoint inhibition. The understanding of the molecular basis for the poor outcome of HNSCC was improved using multi-OMICs approaches, which revealed a strong degree of inter- and intratumor heterogeneity (ITH) at the level of DNA mutations, transcriptome, and (phospho)proteome. Single-cell RNA-sequencing (scRNA-seq) identified RNA-expression signatures related to cell cycle, cell stress, hypoxia, epithelial differentiation, and a partial epithelial-to-mesenchymal transition (pEMT). The latter signature was correlated to nodal involvement and adverse clinical features. Mechanistically, shifts towards a mesenchymal phenotype equips tumor cells with migratory and invasive capacities and with an enhanced resistance to standard therapy. Hence, gradual variations of EMT as observed in HNSCC represent a potent driver of tumor progression that could open new paths to improve the stratification of patients and to innovate approaches to break therapy resistance. These aspects of molecular heterogeneity will be discussed in the present review.
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