美国斯隆凯特琳学院Tuomas Tammela团队开发出高可塑性细胞状态在肺癌中的关键作用。这一研究成果于2026年1月21日发表在国际顶尖学术期刊《自然》上。

在这里，小组开发了能够在体内检测、纵向谱系追踪和消融自体肺肿瘤中HPCS的小鼠模型。谱系追踪显示，HPCS细胞具有高度的细胞状态转换能力，可以在原位产生早期肿瘤（分化）和进展的肺癌细胞状态。纵向谱系追踪主题分泌的荧光素酶显示，与普通癌细胞或其他具有分化肺上皮特征的癌细胞状态相比，HPCS来源的细胞具有较高的生长能力。在早期肿瘤中消融HPCS细胞可消除良性向恶性的转变，而在已建立的肿瘤中，通过自杀基因或嵌合抗原受体（CAR） T细胞消融可显著减轻肿瘤负担。

该团队进一步证明，HPCS引起了治疗耐药细胞状态，而HPCS消融抑制了对化疗和癌蛋白靶向治疗的耐药。值得注意的是，HPCS样状态在再生上皮细胞和多种其他组织的癌中普遍存在，揭示了可塑性程序的趋同。他们的工作建立了HPCS作为一个关键枢纽，使癌细胞状态之间的相互转换。在肺癌和其他癌症中靶向HPCS可能会抑制癌症进展并消除治疗耐药性。

据悉，可塑性——细胞经历表型转变的能力——驱动癌症进展和治疗耐药性。最近的研究表明，实体肿瘤的可塑性集中在一小部分癌细胞中，但缺乏对这种原位高可塑性细胞状态（HPCS）的功能研究。

附：英文原文

Title: Critical role for a high-plasticity cell state in lung cancer

Author: Chan, Jason E., Pan, Chun-Hao, Rub, Jonathan, Guzman, Gary, Krause, Klavdija, Brown, Emma, Zhang, Zeda, Styers, Hannah, Hartmann, Griffin, Li, Zhuxuan, Zhuang, Xueqian, Lowe, Scott W., Betel, Doron, Yan, Yan, Tammela, Tuomas

Issue&Volume: 2026-01-21

Abstract: Plasticity—the ability of cells to undergo phenotypic transitions—drives cancer progression and therapy resistance1,2,3. Recent studies have suggested that plasticity in solid tumours is concentrated in a minority subset of cancer cells4,5,6, yet functional studies examining this high-plasticity cell state (HPCS) in situ are lacking. Here we develop mouse models enabling the detection, longitudinal lineage tracing and ablation of the HPCS in autochthonous lung tumours in vivo. Lineage tracing reveals that the HPCS cells possess a high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and progressed lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals that HPCS-derived cells have a high capacity for growth compared with bulk cancer cells or another cancer cell state with features of differentiated lung epithelium. Ablation of HPCS cells in early neoplasias abrogates benign-to-malignant transition, whereas ablation in established tumours by suicide gene or chimeric antigen receptor (CAR) T cells robustly reduces tumour burden. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas HPCS ablation suppresses resistance to chemotherapy and oncoprotein-targeted therapy. Notably, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.

DOI: 10.1038/s41586-025-09985-x

Source: https://www.nature.com/articles/s41586-025-09985-x