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.
可塑性——细胞发生表型转变的能力——驱动癌症进展和治疗抵抗¹,²,³。近期研究表明实体瘤中的可塑性集中在少数癌细胞亚群中⁴,⁵,⁶，但针对这种高可塑性细胞状态（HPCS）的原位功能研究尚缺乏。我们开发了小鼠模型，可在体内原位肺癌中实现HPCS的检测、纵向谱系示踪和消融。谱系示踪显示HPCS细胞具有强大的细胞状态转变能力，在原位同时产生早期肿瘤性（分化型）和进展期肺癌细胞状态。利用分泌型荧光素酶进行的纵向谱系示踪表明，与普通癌细胞或具有分化肺上皮特征的其他癌细胞状态相比，HPCS衍生细胞具有更强的增殖能力。在早期瘤变中消融HPCS细胞可阻断良性向恶性的转变，而在已形成的肿瘤中通过自杀基因或嵌合抗原受体（CAR）T细胞消融HPCS则显著减轻肿瘤负荷。我们进一步证明HPCS可产生治疗抵抗性细胞状态，而消融HPCS可抑制对化疗和癌蛋白靶向治疗的耐药性。值得注意的是，HPCS样状态在再生上皮及其他多种组织来源的癌中普遍存在，揭示可塑性程序的趋同性。本研究确立HPCS是实现癌细胞状态双向转换的关键枢纽。靶向肺癌及其他癌种的HPCS或可抑制肿瘤进展并消除治疗抵抗。
Critical role for a high-plasticity cell state in lung cancer
肿瘤(癌症)患者之家