Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo
Abstract
Lung cancer is the leading cause of cancer deaths worldwide with non small-cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Although activating mutations in genes of the RAS-MAPK pathway occur in up to 30% of all NSCLC, the cooperating genetic lesions that are required for lung cancer initiation and progression remain poorly understood. Here we identify a role for the cell polarity regulator Scribble (Scrib) in NSCLC. A survey of genomic databases reveals deregulation of SCRIB in human lung cancer and we show that Scrib(+/-) mutant mice develop lung cancer by 540 days with a penetrance of 43%. To model NSCLC development in vivo, we used the extensively characterized LSL-KRas(G12D) murine model of NSCLC. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS-MAPK signaling. Finally, we provide data consistent with immune infiltration having an important role in the acceleration of tumorigenesis in KRas(G12D) lung tumors following Scrib loss.
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In several cases, conditional knockout or heterozygosity of Scribble accelerates tumorigenesis, e.g., leading to multifocal prostate hyperplasia, and accelerated skin and lung tumorigenesis.
“In several cases, conditional knockout or heterozygosity does accelerate tumorigenesis, e.g., leading to multifocal prostate hyperplasia (Pearson et al., 2011), and accelerated skin and lung tumorigenesis (Elsum et al., 2014; Pearson et al., 2015).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Elsum et al., 2014
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References 54 · Cited by 60
- Authors
- Elsum, I. A., Yates, L. L., Pearson, H. B., Phesse, T. J., Long, F., O'Donoghue, R., Ernst, M., Cullinane, C., & Humbert, P. O.
- Affiliations
- Peter MacCallum Cancer Centre (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- The University of Melbourne (AU)
- Corresponding author
- Humbert, P O
- Venue
- Oncogene
- Published
- 2013-11-25
- Volume
- 33
- Issue
- 48
- Pages
- 5523-5533
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2095370559
- Cited by
- 60
- References
- 54
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 9 · 2018: 8 · 2017: 6 · 2016: 5 · 2015: 8 · 2014: 3
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- Scribble, SCRIB, non-small cell lung cancer, KRAS G12D, RAS/MAPK pathway, tumor progression, cell polarity, tumor immune infiltration, heterozygous loss, mouse tumor model
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, Disease Models, Animal, Enzyme Activation, Heterozygote, Humans, Immunohistochemistry, Lung Neoplasms, Membrane Proteins, Mice, Mutant Strains, Proto-Oncogene Proteins, Immunoblotting, Proto-Oncogene Proteins p21(ras), Disease Progression, Gene Dosage, ras Proteins, Loss of Heterozygosity, Oligonucleotide Array Sequence Analysis, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Mice, Real-Time Polymerase Chain Reaction
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