Data from Activation of Kras<sup>G12D</sup> in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma

Abstract

<div>Abstract<p>We have previously identified alveolar type II cell as the cell-of-origin of Kras<sup>G12D</sup>-induced lung adenocarcinoma using cell lineage–specific inducible Cre mouse models. Using gain-of-function 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 Kras<sup>G12D</sup> activation. Here, we examine the phenotype of type II cells after Kras activation and find evidence for proliferation of cells that coexpress type I and type II markers. Three-dimensional organoid culture and transplantation studies determine that these dual-positive cells are highly plastic and tumor initiating <i>in vivo</i>. RNA sequencing analysis reveals that these dual-positive cells are enriched in Ras/MAPK, EGFR, and Notch pathways. Furthermore, the proliferation of these cells requires active Notch signaling and is inhibited by genetic/chemical Sox2 upregulation. Our findings could provide new therapeutic strategies to target KRAS-activated lung adenocarcinomas.</p>Significance:<p>Identification of progenitor like tumor-initiating cells in KRAS-mutant lung adenocarcinoma may allow development of novel targeted therapeutics.</p></div>