Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Tien, Jean Ching-Yi, Chugh, Seema, Goodrum, Andrew E., Cheng, Yunhui, Mannan, Rahul, Zhang, Yuping, Wang, Lisha, Dommeti, Vijaya L., Wang, Xiaoming, Xu, Alice, Hon, Jennifer, Kenum, Carson, Su, Fengyun, Wang, Rui, Cao, Xuhong, Shankar, Sunita, Chinnaiyan, Arul M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157917/
https://www.ncbi.nlm.nih.gov/pubmed/33972443
http://dx.doi.org/10.1073/pnas.2026104118
_version_ 1783699785067266048
author Tien, Jean Ching-Yi
Chugh, Seema
Goodrum, Andrew E.
Cheng, Yunhui
Mannan, Rahul
Zhang, Yuping
Wang, Lisha
Dommeti, Vijaya L.
Wang, Xiaoming
Xu, Alice
Hon, Jennifer
Kenum, Carson
Su, Fengyun
Wang, Rui
Cao, Xuhong
Shankar, Sunita
Chinnaiyan, Arul M.
author_facet Tien, Jean Ching-Yi
Chugh, Seema
Goodrum, Andrew E.
Cheng, Yunhui
Mannan, Rahul
Zhang, Yuping
Wang, Lisha
Dommeti, Vijaya L.
Wang, Xiaoming
Xu, Alice
Hon, Jennifer
Kenum, Carson
Su, Fengyun
Wang, Rui
Cao, Xuhong
Shankar, Sunita
Chinnaiyan, Arul M.
author_sort Tien, Jean Ching-Yi
collection PubMed
description 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-Kras (G12D/+);p53(f/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 KP(Het)C 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.
format Online
Article
Text
id pubmed-8157917
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-81579172021-05-28 AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer Tien, Jean Ching-Yi Chugh, Seema Goodrum, Andrew E. Cheng, Yunhui Mannan, Rahul Zhang, Yuping Wang, Lisha Dommeti, Vijaya L. Wang, Xiaoming Xu, Alice Hon, Jennifer Kenum, Carson Su, Fengyun Wang, Rui Cao, Xuhong Shankar, Sunita Chinnaiyan, Arul M. Proc Natl Acad Sci U S A Biological Sciences 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-Kras (G12D/+);p53(f/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 KP(Het)C 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. National Academy of Sciences 2021-05-18 2021-05-10 /pmc/articles/PMC8157917/ /pubmed/33972443 http://dx.doi.org/10.1073/pnas.2026104118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Tien, Jean Ching-Yi
Chugh, Seema
Goodrum, Andrew E.
Cheng, Yunhui
Mannan, Rahul
Zhang, Yuping
Wang, Lisha
Dommeti, Vijaya L.
Wang, Xiaoming
Xu, Alice
Hon, Jennifer
Kenum, Carson
Su, Fengyun
Wang, Rui
Cao, Xuhong
Shankar, Sunita
Chinnaiyan, Arul M.
AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
title AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
title_full AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
title_fullStr AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
title_full_unstemmed AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
title_short AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
title_sort ago2 promotes tumor progression in kras-driven mouse models of non–small cell lung cancer
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157917/
https://www.ncbi.nlm.nih.gov/pubmed/33972443
http://dx.doi.org/10.1073/pnas.2026104118
work_keys_str_mv AT tienjeanchingyi ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT chughseema ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT goodrumandrewe ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT chengyunhui ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT mannanrahul ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT zhangyuping ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT wanglisha ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT dommetivijayal ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT wangxiaoming ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT xualice ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT honjennifer ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT kenumcarson ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT sufengyun ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT wangrui ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT caoxuhong ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT shankarsunita ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer
AT chinnaiyanarulm ago2promotestumorprogressioninkrasdrivenmousemodelsofnonsmallcelllungcancer