杜克大学Trudy G. Oliver小组揭示了基底细胞起源解决癌症中神经内分泌簇谱系的可塑性。相关论文于2025年9月17日发表在《自然》杂志上。

使用多种SCLC基因工程动物模型，该研究组证明了基底细胞起源（但不是公认的神经内分泌起源）产生神经内分泌簇样肿瘤，高度概括了人类SCLC。基底源性SCLC的单细胞克隆分析进一步揭示了意想不到的转录状态，包括Atoh1⁺状态，以及神经内分泌簇可塑性的谱系轨迹。在基底细胞中，引入人类簇状SCLC中富集的遗传改变，包括高MYC、PTEN缺失和ASCL1抑制，共同促进簇状肿瘤的发生。944例人类SCLCs的转录组学显示基底样亚群和簇离子细胞样状态，它们共同表明癌症状态和正常基底细胞损伤反应机制之间存在显著的守恒。总之，这些数据表明基底细胞可能是SCLC和其他神经内分泌簇癌的起源，这可以解释神经内分泌簇异质性，为靶向谱系可塑性提供新的见解。

据介绍，神经内分泌细胞和簇状细胞是由ASCL1和POU2F3转录因子的表达定义的罕见的化学感觉上皮细胞系。神经内分泌癌，包括小细胞肺癌（SCLC），经常显示簇样亚群，这一特征与患者预后不良有关。驱动神经内分泌簇瘤的机制、异质性和簇样癌症的起源尚不清楚。

附：英文原文

Title: Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer

Author: Ireland, Abbie S., Xie, Daniel A., Hawgood, Sarah B., Barbier, Margaret W., Zuo, Lisa Y., Hanna, Benjamin E., Lucas-Randolph, Scarlett, Tyson, Darren R., Witt, Benjamin L., Govindan, Ramaswamy, Dowlati, Afshin, Moser, Justin C., Thomas, Anish, Puri, Sonam, Rudin, Charles M., Chan, Joseph M., Elliott, Andrew, Oliver, Trudy G.

Issue&Volume: 2025-09-17

Abstract: Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes1,2,3,4,5,6,7,8,9. The mechanisms driving neuroendocrine–tuft tumour heterogeneity and the origins of tuft-like cancers are unknown. Using multiple genetically engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine–tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovered unexpected transcriptional states, including an Atoh1+ state, and lineage trajectories underlying neuroendocrine–tuft plasticity. Uniquely in basal cells, the introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss and ASCL1 suppression, cooperates to promote tuft-like tumours. Transcriptomics of 944 human SCLCs revealed a basal-like subset and a tuft–ionocyte-like state that altogether demonstrate notable conservation between cancer states and normal basal cell injury response mechanisms10,11,12,13. Together, these data indicate that the basal cell is a probable origin for SCLC and other neuroendocrine–tuft cancers that can explain neuroendocrine–tuft heterogeneity, offering new insights for targeting lineage plasticity.

DOI: 10.1038/s41586-025-09503-z

Source: https://www.nature.com/articles/s41586-025-09503-z