小柯机器人

美国德克萨斯大学Humam Kadara等研究人员合作绘制出肺腺癌上皮细胞状态和可塑性图谱。2024年2月28日，《自然》杂志在线发表了这项成果。

研究人员报道了来自16个早期肺腺癌（LUAD）和47个匹配的正常肺样本的246102个上皮细胞。上皮细胞由不同的正常细胞和癌细胞状态组成，癌细胞的多样性与LUAD特异性致癌驱动因素密切相关。KRAS突变的癌细胞表现出独特的转录特征、分化减弱和低水平的非整倍体。

人类LUAD样本周围的非恶性区域富含肺泡中间细胞，这些细胞表现出KRT8表达升高（即KRT8⁺肺泡中间细胞（KAC））、分化降低、可塑性增强和KRAS驱动基因突变。KAC的表达谱在肺癌前病变细胞和LUAD细胞中富集，标志着存活率低。在暴露于烟草致癌物质的小鼠中，KAC先于肺肿瘤出现，并在停止暴露于致癌物质后持续数月。

此外，在肺泡2型（AT2）细胞衍生的KAC富集器官组织中，它们获得了Kras突变，并传达了对靶向KRAS抑制的敏感性。最后，AT2细胞或KRT8⁺细胞暴露于致癌物质后的谱系标记表明，KAC可能是AT2细胞向肿瘤细胞转化的中间产物。这项研究提供了有关上皮细胞状态的新见解，而这种状态正是LUAD发生的根源，可能是预防或干预的潜在目标。

据悉，人们需要了解早期LUAD发生的细胞过程，以便制定干预策略。

附：英文原文

Title: An atlas of epithelial cell states and plasticity in lung adenocarcinoma

Author: Han, Guangchun, Sinjab, Ansam, Rahal, Zahraa, Lynch, Anne M., Treekitkarnmongkol, Warapen, Liu, Yuejiang, Serrano, Alejandra G., Feng, Jiping, Liang, Ke, Khan, Khaja, Lu, Wei, Hernandez, Sharia D., Liu, Yunhe, Cao, Xuanye, Dai, Enyu, Pei, Guangsheng, Hu, Jian, Abaya, Camille, Gomez-Bolanos, Lorena I., Peng, Fuduan, Chen, Minyue, Parra, Edwin R., Cascone, Tina, Sepesi, Boris, Moghaddam, Seyed Javad, Scheet, Paul, Negrao, Marcelo V., Heymach, John V., Li, Mingyao, Dubinett, Steven M., Stevenson, Christopher S., Spira, Avrum E., Fujimoto, Junya, Solis, Luisa M., Wistuba, Ignacio I., Chen, Jichao, Wang, Linghua, Kadara, Humam

Issue&Volume: 2024-02-28

Abstract: Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

DOI: 10.1038/s41586-024-07113-9

Source: https://www.nature.com/articles/s41586-024-07113-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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