Prkci-Ect2 gain drives lung adenocarcinoma metastasis and lineage infidelity through enhanced cellular plasticity

Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is characterized by extensive tumor heterogeneity, early metastatic spread, and poor response to therapeutic intervention. The oncogenic KrasG12D and Trp53 loss (KP) mouse model recapitulates many aspects of LUAD tumorigenesis, however these mice rarely develop distant metastases and fail to exhibit the progenitor-like tumor cell states associated with human LUAD metastases. Emerging evidence indicates that exhibit a high degree of cellular plasticity, enabling them to effectively adapt to and overcome the diverse barriers of the metastatic cascade. However, the oncogenic events that drive cell plasticity and link tumor cell states to metastatic progression remain poorly defined. We have identified Protein Kinase C iota (PRKCI) and Epithelial Cell Transforming Sequence 2 (ECT2) as cooperative oncogenes in LUAD. PKCι directly phosphorylates and activates ECT2, while copy number gain (CNG) of PRKCI and ECT2 within the recurrent 3q26 amplicon drives their coordinated overexpression in ~30% of human LUADs and is associated with poor survival. To model PRKCI-ECT2 CNG, we generated KP mice harboring conditional knock in alleles of Prkci and Ect2 (KP-Gain). Prkci-Ect2 gain fundamentally alters LUAD biology by promoting cell plasticity through progressive dedifferentiation along the lung developmental pathway in a cell of origin dependent manner. Specifically, KP-Gain tumors initiated from alveolar type II (AT2) cells dedifferentiate into a distal SOX9-high progenitor-like cell state, exhibit increased tumor size and grade, and harbor frequent metastases to the liver. Interestingly, KP-Gain tumors initiated in bronchiolar club cells undergo further reprogramming, giving rise to a more primitive foregut SOX2-high progenitor-like state. Club cell-derived KP-Gain tumors are markedly more aggressive and exhibit extreme lineage infidelity giving rise to adeno-squamous carcinoma, small cell lung cancer and pleomorphic carcinomas, and display both liver and brain metastasis. Taken together, our results indicate that Prkci-Ect2 gain promotes primary LUAD tumor progression, distant metastasis, and histological infidelity by driving tumor cells into more primordial lung developmental cell states.