Cancer cells exhibit a remarkable ability to undergo phenotypic transitions, adapt to stressors, and develop resistance to therapy. A recent study published in Nature identified a small but highly potent subpopulation of lung cancer cells that appears to orchestrate these behaviors, highlighting a promising new target for cancer therapy. The researchers focused on cellular diversity, the capacity of cancer cells to transition between different functional states.Â
Although previous studies suggested that only a limited number of tumor cells are highly plastic, their direct contribution to cancer progression has not been established. In this study, the researchers describe a distinct high-plasticity cell state (HPCS) that functions as a central hub for tumor growth, disease progression, and therapeutic resistance in lung adenocarcinoma.
The researchers developed tools to label, track, and selectively eliminate HPCS cells in living tumors using genetically engineered mouse models of lung cancer. HPCS cells were characterized by Slc4a11 expression, which was a reliable gene marker of the plastic cell population in the autochthonous lung tumors. At 15-16 weeks of tumor development, HPCS cells accounted for 17±4.3% of cancer cells, closely matching previous single-cell RNA sequencing estimates of 13.1±1.6%. Experiments of the lineage-tracing found that HPCS cells are highly dynamic; although the overall proportion of HPCS cells remains relatively steady, individual cells rapidly transition to other cancer cell forms. Within 14 days, traced HPCS cells give rise to a broad array of phenotypes, with at least half transforming into early neoplastic or other more advanced malignant states. Quantitative analysis demonstrated that this diversification subsequently increases tumour cell heterogeneity, establishing HPCS as a major source of cellular diversity.
Interestingly, HPCS cells themselves are largely dormant and rarely divide. Instead, they promote tumour growth by generating highly proliferative progeny. Only 3 days after leaving the HPCS, 9.1 ±2.7% of these derivative cells were actively cycling, rising to 15.1± 1.8% by 14 days, whereas the proliferation rates in non-HPCS tumor cells remained relatively constant. The functional significance of the HPCS was confirmed through selective ablation; eliminating HPCS cells during the early tumor formation did not decrease the number of the primary lesions but significantly inhibited the tumor growth. Large neoplastic lesions (over >0.15 mm2) were nearly absent, and the progression from benign atypical adenomatous hyperplasia to more aggressive adenomas was strongly suppressed. Ablation of HPCS cells also significantly decreased total tumor burden in established tumors.Â
The study further linked HPCS to therapy resistance. HPCS cells can adopt states that survive chemotherapy and targeted therapies, whereas their elimination reduces the development of resistant populations, indicating that HPCS lies at the centre of treatment failure. High-plasticity cell states were also observed in regenerating epithelial tissues and in cancers from multiple organs, suggesting that similar plasticity programs may operate broadly across carcinomas.
Collectively, these findings place the high-plasticity cell state at the core of lung cancer evolution. HPCS cells drive tumor growth, adaptation, and therapy resistance by acting as a transitional hub between cancer cell identities. Targeting the downstream effects of these cells, rather than individual cell types, may offer a novel approach to suppressing cancer progression and combating drug resistance.Â
Reference: Chan JE, Pan CH, Rub J, et al. Critical role for a high-plasticity cell state in lung cancer. Nature. 2026. doi:10.1038/s41586-025-09985-xÂ
