Journal article
Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis
Cancer research (Chicago, Ill.), Vol.82(22), pp.4261-4273
11/15/2022
DOI: 10.1158/0008-5472.CAN-21-3214
PMCID: PMC9664136
PMID: 36112789
Abstract
Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a pre-dictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engi-neered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emer-gence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously impli-cated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression of Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/(3-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of The Cancer Genome Atlas patient samples revealed that chromosome 3p24, which encompasses RBMS3, is frequently lost in non-small cell lung cancer and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest that RBMS3 silencing may contribute to malignant NSCLC progression.Significance: Loss of RBMS3 cooperates with BRAFV600E to induce lung tumorigenesis, providing a deeper understanding of the molecular mechanisms underlying mutant BRAF-driven lung cancer and potential strategies to more effectively target this disease.
Details
- Title: Subtitle
- Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis
- Creators
- Aria Vaishnavi - University of UtahJoseph Juan - Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USAMaebh Jacob - University of UtahChristopher Stehn - University of UtahEric E. Gardner - Weill Cornell MedicineMichael T. Scherzer - University of UtahSophia Schuman - University of UtahJ. Edward Van Veen - University of UtahBrandon Murphy - University of UtahChristopher S. Hackett - Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USAAdam J. Dupuy - Univ Iowa, Dept Anat & Cell Biol, Iowa City, IA USASteven A. Chmura - Weill Cornell MedicineLouise van der Weyden - Wellcome Sanger InstituteJustin Y. Newberg - H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL USAAnnie Liu - University of UtahKaren Mann - H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL USAAlistair G. Rust - Wellcome Sanger InstituteWilliam A. Weiss - Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USAConan G. Kinsey - University of UtahDavid J. Adams - University of UtahAllie Grossmann - University of UtahMichael B. Mann - H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL USAMartin McMahon - University of Utah
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.82(22), pp.4261-4273
- DOI
- 10.1158/0008-5472.CAN-21-3214
- PMID
- 36112789
- PMCID
- PMC9664136
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 13
- Grant note
- Genentech Foundation Graduate Fellowship Award R01 CA131261; F32 CA228267; K99 CA246084 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 21717 / Cancer Research UK
- Language
- English
- Date published
- 11/15/2022
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984321947402771
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