Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer.
Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer.
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DOI：
10.1038/s12276-022-00905-x
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发表时间：
2022-12
影响因子：
12.8
通讯作者：
Park, Kwon-Sik
中科院分区：
文献类型：
--
作者：
Kirk, Nicole A.;Kim, Kee-Beom;Park, Kwon-Sik
肿瘤抑制基因（TSGs）通常参与维持体内平衡。肿瘤抑制功能的丧失导致细胞可塑性，从而导致多种类型的癌症，包括小细胞肺癌（SCLC），一种侵袭性类型的肺癌。SCLC在很大程度上是由TSG中的许多功能丧失突变驱动的，通常在编码染色质修饰剂的那些中。这些突变提出了治疗挑战，因为它们不能直接起作用。或者，了解由此产生的分子变化可能会提供深入了解肿瘤干预策略。我们假设，尽管SCLC的基因组结构异质，但患者肿瘤中突变的影响与导致恶性肿瘤的几个重要途径有关。具体而言，染色质修饰剂的改变导致转录失调，将突变细胞推向高度可塑性状态，使其具有免疫逃避性和高度转移性。这篇综述将突出染色质修饰剂与相反功能的不平衡导致免疫识别标记物的丢失，有效地从免疫系统中掩蔽肿瘤细胞的研究。本文还讨论了染色质修饰剂在维持神经内分泌特性中的作用，以及异常转录控制在肿瘤发生和发展过程中促进上皮细胞向间质细胞转化中的作用。虽然这些途径被认为是不同的，我们强调，这些途径往往共享分子驱动程序和介质。了解频繁改变的染色质修饰剂之间的关系将为SCLC发展和进展的分子机制提供有价值的见解，因此可能揭示SCLC和具有类似突变的其他癌症的预防和治疗弱点。研究突变的蛋白质复合物如何在小细胞肺癌（SCLC）期间触发免疫逃避，可以为这种难治性疾病提供可能的治疗方法。SCLC是由肿瘤抑制基因的功能丧失突变驱动的，这反过来又改变了染色质修饰剂的活性，改变染色质的蛋白质复合物，DNA和蛋白质的混合物形成染色体。位于美国夏洛茨维尔的弗吉尼亚大学的Kwon-Sik Park及其同事回顾了目前对相关机制的理解。研究表明，不同染色质修饰基团的不平衡可能导致肿瘤识别标记物的丢失，从而有效地将肿瘤细胞隐藏在免疫系统之外。一种特定染色质修饰剂的过度活跃调节癌细胞的可塑性，将细胞从上皮细胞转移到不太专业的类型，这意味着它们可以更快地分化和扩散到全身。
Tumor suppressor genes (TSGs) are often involved in maintaining homeostasis. Loss of tumor suppressor functions causes cellular plasticity that drives numerous types of cancer, including small-cell lung cancer (SCLC), an aggressive type of lung cancer. SCLC is largely driven by numerous loss-of-function mutations in TSGs, often in those encoding chromatin modifiers. These mutations present a therapeutic challenge because they are not directly actionable. Alternatively, understanding the resulting molecular changes may provide insight into tumor intervention strategies. We hypothesize that despite the heterogeneous genomic landscape in SCLC, the impacts of mutations in patient tumors are related to a few important pathways causing malignancy. Specifically, alterations in chromatin modifiers result in transcriptional dysregulation, driving mutant cells toward a highly plastic state that renders them immune evasive and highly metastatic. This review will highlight studies in which imbalance of chromatin modifiers with opposing functions led to loss of immune recognition markers, effectively masking tumor cells from the immune system. This review also discusses the role of chromatin modifiers in maintaining neuroendocrine characteristics and the role of aberrant transcriptional control in promoting epithelial-to-mesenchymal transition during tumor development and progression. While these pathways are thought to be disparate, we highlight that the pathways often share molecular drivers and mediators. Understanding the relationships among frequently altered chromatin modifiers will provide valuable insights into the molecular mechanisms of SCLC development and progression and therefore may reveal preventive and therapeutic vulnerabilities of SCLC and other cancers with similar mutations. Investigating how mutated protein complexes trigger immune evasion during small-cell lung cancer (SCLC) could yield possible therapeutic approaches for this intractable disease. SCLC is driven by loss-of-function mutations in tumour suppressor genes, which in turn alter the activity of chromatin modifiers, protein complexes that alter chromatin, the mixture of DNA and proteins forming chromosomes. Kwon-Sik Park at the University of Virginia in Charlottesville, USA, and co-workers have reviewed current understanding of the mechanisms involved. Studies show that imbalances in different chromatin modifier groups can result in the loss of tumour recognition markers, effectively hiding tumour cells from the immune system. The hyperactivity of one specific chromatin modifier regulates cancer cell plasticity, shifting cells from epithelial to a less specialised type, meaning they can differentiate and spread through the body more quickly.
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