Protein Kinase C? dictates tumor trajectory, cell state plasticity and immune surveillance in lung adenocarcinoma

By genetically ablating oncogenic PKC? in a Kras/Trp53-driven lung adenocarcinoma mouse model, we identify two distinct tumor trajectories that resemble lung development and lung regeneration, respectively. Mechanistically, loss of PKC? expression leads to the accumulation of senescent tumor cells with transcriptional similarities to the pre-AT1 transitional cell state (PATS) observed during alveolar regeneration after injury. In addition to inhibiting cellular plasticity through stable proliferation arrest, senescent PATS-like tumor cells induce formation of large, organized aggregates of immune cells called tertiary lymphoid structures (TLS) within KPI tumors. Overall design: Individual tumors were microdissected from ~30-week KP (KrasG12D/Trp53fl/fl) and ~40-week KPI (KrasG12D/Trp53fl/fl/Prkcifl/fl) animals (n = 5 tumors/animal; 2 animals/genotype). After removal of endothelial cells, red blood cells, and dead cells, scRNA-seq was performed on tumor samples containing both cancer and immune cells.