High-Plasticity Cell State Drives Lung Cancer Progression and Drug Resistance

A growing body of literature supports that phenotypic plasticity is associated with disease progression and therapeutic resistance, but whether specific, highly plastic states are functionally required in vivo remains unresolved. Chan, Pan, and colleagues developed mouse models of KrasG12D-mutant, Trp53-null (KP) lung adenocarcinoma, genetically engineered to enable longitudinal lineage tracing of tumor cells in a malignant high-plasticity cell state (HPCS) via a fluorescent reporter inserted into the Slc4a11 locus, specifically expressed in the HPCS. This reporter cassette included the diphtheria toxin (DT) receptor, for DT-inducible HPCS ablation. The KP lung adenocarcinoma model also comprised multiple secreted luciferases, which allowed the longitudinal sampling of lineage-traced cells, with luciferase activity in the plasma serving as a measure of HPCS versus non-HPCS cancer cell growth. Lineage tracing revealed that HPCS cells gave rise to all cancer cell states observed in precursor adenomas and later-stage adenocarcinomas, positioning the HPCS as a transition hub. Lineage-traced HPCS cells rapidly exited the HPCS, and although HPCS cells were quiescent, HPCS derivatives exhibited greater long-term growth potential than bulk tumor cells. Notably, non-HPCS tumor cells could acquire the HPCS, thus differentiating the HPCS from the hierarchy expected of a cancer stem cell model. Ablation of HPCS cells blocked benign-to-malignant progression in early lesions and reduced tumor burden in established lung adenocarcinomas, providing evidence that the HPCS was functionally required throughout lung progression. Moreover, HPCS cells were implicated in the context of therapeutic resistance, as cisplatin or pharmacologic KRASG12D inhibition preferentially depleted non-HPCS cells. While HPCS cells were not intrinsically resistant to either therapy, these cells gave rise to therapy-resistant states and seeded minimal residual disease. HPCS ablation, either through DT-induced ablation or CAR T cell–mediated targeting of the HPCS-specific surface receptor uPAR, increased the in vivo efficacy of cisplatin or KRASG12D inhibition. As the HPCS in lung cancer shared similarities with plastic states observed in other human carcinomas as well as the regenerative program activated upon lung injury, these findings together suggest that the HPCS, potentially a program conserved across cancer and physiological injury responses, functionally contributes to tumor progression and therapeutic resistance.Chan JE, Pan C-H, Rub J, Guzman G, Krause K, Brown E, et al. Critical role for a high-plasticity cell state in lung cancer. Nature 2026 Jan 21 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.