Involvement of Epithelial-Mesenchymal Transition Genes in Small Cell Lung Cancer Phenotypic Plasticity.
Involvement of Epithelial-Mesenchymal Transition Genes in Small Cell Lung Cancer Phenotypic Plasticity.
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小细胞肺癌（SCLC）是一种侵袭性癌症，难以治疗。根据基因表达特征，至少有五种SCLC细胞亚型。这些亚型之间的转换和它们之间的合作有助于SCLC的进展。特别地，神经内分泌（NE）状态（包括A、A2和N亚型）与非NE状态（包括P和Y亚型）之间的转变是SCLC可塑性的标志。本研究分析了SCLC亚型与上皮间质转化（EMT）的关系。EMT是一种众所周知的细胞可塑性形式，有助于癌症的侵袭和抵抗。结果表明，SCLC-A2亚型是上皮细胞，而SCLC-A和SCLC-N是间充质细胞，但与非NE间充质状态不同。本研究为了解SCLC肿瘤可塑性的基因调控机制及其对其他癌症类型的适用性提供了基础。小细胞肺癌（SCLC）是一种侵袭性癌症，主要由上皮性肺神经内分泌（NE）细胞引起。肿瘤内异质性在SCLC疾病进展、转移和治疗抗性中起关键作用。最近通过基因表达特征定义了至少五种转录SCLC NE和非NE细胞亚型。从NE到非NE细胞状态的转变和肿瘤内亚型之间的合作可能通过适应扰动的机制促进SCLC进展。因此，区分SCLC亚型或促进转变的基因调控程序引起了极大的兴趣。在这里，我们系统地分析了SCLC NE/非NE转换和上皮间质转化（EMT）之间的关系-一个研究充分的细胞过程，有助于癌症的侵袭性和耐药性-使用多个转录组数据集从SCLC小鼠肿瘤模型，人类癌细胞系，和肿瘤样本。NE SCLC-A2亚型映射到上皮状态。相反，SCLC-A和SCLC-N（NE）映射到部分间充质状态（M1），其不同于非NE部分间充质状态（M2）。SCLC亚型和EMT计划之间的对应关系为进一步了解SCLC肿瘤可塑性的基因调控机制铺平了道路，适用于其他癌症类型。
Small cell lung cancer (SCLC) is an aggressive cancer that is difficult to treat. There are at least five subtypes of SCLC cells, defined by gene expression signatures. The transitions between these subtypes and cooperation between them contribute to the progression of SCLC. Particularly, transitions between neuroendocrine (NE) states, including A, A2, and N subtypes, and the non-NE states, including P and Y subtypes, are hallmarks of SCLC plasticity. In this study, the relationship between SCLC subtypes and epithelial to mesenchymal transition (EMT) was analyzed. EMT is a well-known form of cellular plasticity that contributes to cancer invasiveness and resistance. The results showed that the SCLC-A2 subtype is epithelial while SCLC-A and SCLC-N are mesenchymal but distinct from the non-NE mesenchymal states. This study provides a basis for understanding the gene regulatory mechanisms of SCLC tumor plasticity and its applicability to other cancer types. Small cell lung cancer (SCLC) is an aggressive cancer recalcitrant to treatment, arising predominantly from epithelial pulmonary neuroendocrine (NE) cells. Intratumor heterogeneity plays critical roles in SCLC disease progression, metastasis, and treatment resistance. At least five transcriptional SCLC NE and non-NE cell subtypes were recently defined by gene expression signatures. Transition from NE to non-NE cell states and cooperation between subtypes within a tumor likely contribute to SCLC progression by mechanisms of adaptation to perturbations. Therefore, gene regulatory programs distinguishing SCLC subtypes or promoting transitions are of great interest. Here, we systematically analyze the relationship between SCLC NE/non-NE transition and epithelial to mesenchymal transition (EMT)—a well-studied cellular process contributing to cancer invasiveness and resistance—using multiple transcriptome datasets from SCLC mouse tumor models, human cancer cell lines, and tumor samples. The NE SCLC-A2 subtype maps to the epithelial state. In contrast, SCLC-A and SCLC-N (NE) map to a partial mesenchymal state (M1) that is distinct from the non-NE, partial mesenchymal state (M2). The correspondence between SCLC subtypes and the EMT program paves the way for further work to understand gene regulatory mechanisms of SCLC tumor plasticity with applicability to other cancer types.
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