文章：

小细胞肺癌异质性和表型可塑性的挑战

Challenges of small cell lung cancer heterogeneity and phenotypic plasticity

原文发布日期：2025-04-10

DOI: 10.1038/s41568-025-00803-0

类型: Review Article

开放获取: 否

英文摘要：

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with ~7% 5-year overall survival reflecting early metastasis and rapid acquired chemoresistance. Immunotherapy briefly extends overall survival in ~15% cases, yet predictive biomarkers are lacking. Targeted therapies are beginning to show promise, with a recently approved delta-like ligand 3 (DLL3)-targeted therapy impacting the treatment landscape. The increased availability of patient-faithful models, accumulating human tumour biobanks and numerous comprehensive molecular profiling studies have collectively facilitated the mapping and understanding of substantial intertumoural and intratumoural heterogeneity. Beyond the almost ubiquitous loss of wild-type p53 and RB1, SCLC is characterized by heterogeneously mis-regulated expression of MYC family members, yes-associated protein 1 (YAP1), NOTCH pathway signalling, anti-apoptotic BCL2 and epigenetic regulators. Molecular subtypes are based on the neurogenic transcription factors achaete-scute homologue 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), the rarer non-neuroendocrine transcription factor POU class 2 homeobox 3 (POU2F3), and immune- and inflammation-related signatures. Furthermore, SCLC shows phenotypic plasticity, including neuroendocrine-to-non-neuroendocrine transition driven by NOTCH signalling, which is associated with disease progression, chemoresistance and immune modulation and, in mouse models, with metastasis. Although these features pose substantial challenges, understanding the molecular vulnerabilities of transcription factor subtypes, the functional relevance of plasticity and cell cooperation offer opportunities for personalized therapies informed by liquid and tissue biomarkers.

摘要翻译： 

小细胞肺癌（SCLC）是一种侵袭性神经内分泌恶性肿瘤，其5年总生存率约为7%，反映出早期转移和快速获得性化疗耐药的特点。免疫疗法仅在约15%的病例中短暂延长总生存期，但目前仍缺乏预测性生物标志物。靶向治疗开始展现潜力，近期获批的靶向δ样配体3（DLL3）疗法正在改变治疗格局。患者真实性模型的普及、人类肿瘤生物样本库的积累以及大量综合性分子图谱研究，共同促进了对肿瘤间和肿瘤内异质性的绘制与理解。除几乎普遍存在的野生型p53和RB1缺失外，SCLC的特征还包括MYC家族成员、Yes相关蛋白1（YAP1）、NOTCH通路信号传导、抗凋亡蛋白BCL2及表观遗传调控因子的异质性失调表达。其分子亚型基于神经源性转录因子achaete-scute同源物1（ASCL1）和神经源性分化因子1（NEUROD1）、较罕见的非神经内分泌转录因子POU2F3，以及免疫和炎症相关特征。此外，SCLC表现出表型可塑性，包括由NOTCH信号驱动的神经内分泌向非神经内分泌转化，该过程与疾病进展、化疗耐药和免疫调节相关，并在小鼠模型中与转移有关。尽管这些特征带来重大挑战，但通过液体和组织生物标志物解读转录因子亚型的分子脆弱性、可塑性的功能意义及细胞协作机制，为个性化治疗提供了新的机遇。

原文链接：

Challenges of small cell lung cancer heterogeneity and phenotypic plasticity