title: 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.
authors.affiliation: Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: I A
authors.initials: IA
authors.lastname: Elsum
authors.affiliation: Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: L L
authors.initials: LL
authors.lastname: Yates
authors.affiliation: 1] Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia [2] The Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia.
authors.forename: H B
authors.initials: HB
authors.lastname: Pearson
authors.affiliation: Cell Signaling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Phesse
authors.affiliation: Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Long
authors.affiliation: Cell Signaling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: R
authors.initials: R
authors.lastname: O'Donoghue
authors.affiliation: Cell Signaling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Ernst
authors.affiliation: 1] The Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia [2] Translational Research Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: 1] Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia [2] The Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia [3] Department of Pathology, University of Melbourne, Parkville, Victoria, Australia [4] Department of Molecular Biology and Biochemistry, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: P O
authors.initials: PO
authors.lastname: Humbert
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D018628:Gene Dosage; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C117307:KRAS protein, human; C480591:SCRIB protein, human; C508433:scrib protein, mouse; C495971:Hras protein, mouse