Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo

Elsum, I. A., Yates, L. L., Pearson, Helen B., Phesse, Toby, 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

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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:	Biosciences
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Nature Publishing
ISSN:	0950-9232
Date of Acceptance:	14 October 2013
Last Modified:	24 Jul 2019 20:26
URI:	http://orca-mwe.cf.ac.uk/id/eprint/91566

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