PRKCI-ECT2 copy number gain promotes developmental reprogramming and metastatic competence in lung adenocarcinoma.
Lung adenocarcinoma (LUAD) shows extensive lineage plasticity and early metastatic dissemination, but the oncogenic events that actively drive these processes remain poorly defined. Here, we identify coordinated PRKCI and ECT2 copy number gain, present in approximately 30% of human LUADs, as a driver of developmental reprogramming and metastasis. Using a genetically engineered mouse model that recapitulates PRKCI-ECT2 gain in Kras/Trp53-driven LUAD, we show that elevated PKCι-ECT2 signaling rewires tumor trajectory in a cell-of-origin-dependent manner. Alveolar type II cell-derived tumors dedifferentiate into a distal SOX9high progenitor-like state associated with aggressive growth and liver metastasis, whereas club cell-derived tumors transition into a foregut SOX2high progenitor-like state that supports lineage infidelity and histological transformation. Human LUAD analyses support these progenitor programs as clinically relevant features of PRKCI-ECT2 gain.