American Association for Cancer Research
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Supplementary Figure S6 from Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma

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journal contribution
posted on 2023-11-24, 14:40 authored by Priyanka Chaudhary, Xia Xu, Guangfang Wang, Jacob P. Hoj, Rishi R. Rampersad, Marie-Liesse Asselin-Labat, Stephanie Ting, William Kim, Pablo Tamayo, Ann Marie Pendergast, Mark W. Onaitis

RepSox treatment increases Sox2 levels while TGFb remains unchanged in KrasG12D mutant lungs


HHS | NIH | NCI | National Cancer Institute (NCI)

VA | Veterans Affairs San Diego Healthcare System (VASDHS)



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-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 KrasG12D 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 in vivo. 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. Identification of progenitor like tumor-initiating cells in KRAS-mutant lung adenocarcinoma may allow development of novel targeted therapeutics.