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Journal article
Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth
Nature cell biology, v 25(1)
Jan 2023
PMID: 36635501
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRAS
-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer.
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Details
- Title
- Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth
- Creators
- Rui Tang - Stanford UniversityEmily G Shuldiner - Stanford UniversityMarcus Kelly - Stanford UniversityChristopher W Murray - Stanford UniversityJess D Hebert - Stanford UniversityLaura Andrejka - Stanford UniversityMin K Tsai - Stanford UniversityNicholas W Hughes - Stanford UniversityMitchell I Parker - Fox Chase Cancer CenterHongchen Cai - Stanford UniversityYao-Cheng Li - Salk Institute for Biological StudiesGeoffrey M Wahl - Salk Institute for Biological StudiesRoland L Dunbrack - Fox Chase Cancer CenterPeter K Jackson - Stanford UniversityDmitri A Petrov - Stanford UniversityMonte M Winslow - Stanford University
- Publication Details
- Nature cell biology, v 25(1)
- Publisher
- Springer Nature
- Grant note
- GM142263 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01-CA231253 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA250534 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) 28FT-0019 / Tobacco-Related Disease Research Program (TRDRP) R35 GM122517 / NIGMS NIH HHS 27IP-0052 / Tobacco-Related Disease Research Program (TRDRP) R35 CA197687 / NCI NIH HHS R01-CA234349 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P30-CA124435 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) K99 CA256039 / NCI NIH HHS T31FT1619 / Tobacco-Related Disease Research Program (TRDRP) CA006927 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) GM122517 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) F30 GM142263 / NIGMS NIH HHS K99CA256039 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:000937032400001
- Scopus ID
- 2-s2.0-85146186672
- Other Identifier
- 991020099743704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology