Activation of KrasG12D in subset of alveolar Type II cells enhances cellular plasticity in lung adenocarcinoma.

We have previously identified alveolar Type II cell as the cell-of-origin of KrasG12D induced lung adenocarcinoma using cell-lineage specific inducible Cre mouse models. Using gain and loss of function genetic models, we discovered that active Notch signaling and low Sox2 levels dictate the ability of Type II cells to proliferate and progress into lung adenocarcinoma upon KrasG12D activation. Here, we examine the phenotype of Type II cells after Kras activation and find evidence for proliferation of cells that co-express Type I and Type II markers. 3D organoid culture and transplantation studies determine that these dual positive cells are highly plastic and tumor-initiating in vivo. RNAseq analysis reveals that these dual positive cells are enriched in Ras/MAPK, EGFR and Notch pathways. Further, the proliferation of these cells requires active Notch signaling and is inhibited by genetic/chemical Sox2 up-regulation. Our findings could provide new therapeutic strategies to target KRAS-activated lung adenocarcinomas.