Journal Article

AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer

Cao, Xuhong, Mannan, Rahul, Wang, Lisha, Shankar, Sunita, Chugh, Seema, Xu, Alice, Goodrum, Andrew E., Su, Fengyun, Wang, Rui, Kenum, Carson, Cheng, Yunhui, Chinnaiyan, Arul M., Hon, Jennifer, Zhang, Yuping, Tien, Jean Ching-Yi, Dommeti, Vijaya L., Wang, Xiaoming

2021

Overview

Lung cancer is the deadliest malignancy in the United States. Non–small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA-induced silencing complex (RISC)—physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-KrasG12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell–specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance.

• Publisher: National Academy of Sciences
• Subject: Ablation / Alleles / Animal models / Animals / Argonaute 2 protein / Argonaute Proteins - physiology / Biological Sciences / Carcinoma, Non-Small-Cell Lung - etiology / Carcinoma, Non-Small-Cell Lung - genetics / Cell culture / Disease Models, Animal / Disease Progression / Gene sequencing / In vivo methods and tests / K-Ras protein / Lung cancer / Lung Neoplasms - etiology / Lung Neoplasms - genetics / Malignancy / MAP Kinase Signaling System / Medical Sciences / Mice / Mice, Inbred C57BL / Mutation / Nodules / Non-small cell lung carcinoma / Organoids / p53 Protein / Phosphorylation / Proto-Oncogene Proteins p21(ras) - physiology / Ribonucleic acid / RNA / RNA-induced silencing complex / RNA-mediated interference / Signal Transduction - physiology / Signaling / Small cell lung carcinoma / Trachea / Tumor cells / Tumors