Elsum, I. A., Yates, L. L., Pearson, H. B.  ORCID: https://orcid.org/0000-0002-3284-0843, Phesse, T. J. ORCID: https://orcid.org/0000-0001-9568-4916, Long, F., O'Donoghue, R., Ernst, M., Cullinane, C. and Humbert, P. O.
2014.
Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo.
Oncogene
33
(48)
, pp. 5523-5533.
10.1038/onc.2013.498
|
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-KRasG12D 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 KRasG12D lung tumors following Scrib loss.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Biosciences Research Institutes & Centres > European Cancer Stem Cell Research Institute (ECSCRI) |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Publisher: | Springer Nature |
| ISSN: | 0950-9232 |
| Date of Acceptance: | 14 October 2013 |
| Last Modified: | 18 Sep 2023 06:30 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/91566 |
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