title: Loss of the keratin cytoskeleton is not sufficient to induce epithelial mesenchymal transition in a novel KRAS driven sporadic lung cancer mouse model.
abstract: Epithelial-to-mesenchymal transition (EMT), the phenotypical change of cells from an epithelial to a mesenchymal type, is thought to be a key event in invasion and metastasis of adenocarcinomas. These changes involve loss of keratin expression as well as loss of cell polarity and adhesion. We here aimed to determine whether the loss of keratin expression itself drives increased invasion and metastasis in adenocarcinomas and whether keratin loss leads to the phenotypic changes associated with EMT. Therefore, we employed a recently described murine model in which conditional deletion of the Keratin cluster II by Cre-recombinase leads to the loss of the entire keratinmultiprotein family. These mice were crossed into a newly generated Cre-recombinase inducible KRAS-driven murine lung cancer model to examine the effect of keratin loss on morphology, invasion and metastasis as well as expression of EMT related genes in the resulting tumors. We here clearly show that loss of a functional keratin cytoskeleton did not significantly alter tumor morphology or biology in terms of invasion, metastasis, proliferation or tumor burden and did not lead to induction of EMT. Further, tumor cells did not induce synchronously expression of vimentin, which is often seen in EMT, to compensate for keratin loss. In summary, our data suggest that changes in cell shape and migration that underlie EMT are dependent on changes in signaling pathways that cause secondary changes in keratin expression and organization. Thus, we conclude that loss of the keratin cytoskeleton per se is not sufficient to causally drive EMT in this tumor model.
authors.affiliation: Institute of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: König
authors.forename: Lydia
authors.initials: L
authors.lastname: Meder
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kröger
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.forename: Ursula
authors.initials: U
authors.lastname: Rommerscheidt-Fuss
authors.forename: Philip
authors.initials: P
authors.lastname: Kahl
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Magin
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D018390:Gene Targeting; D011905:Genes, ras; D006801:Humans; D007633:Keratins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000473:pathology
chemical_list: D015415:Biomarkers; D007633:Keratins
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Pathol Int. 2012 Apr;62(4):232-45
references.pmid: 22449227
references.citation: Pathol Res Pract. 2003;199(3):159-63
references.pmid: 12812317
references.citation: Ann Thorac Surg. 2011 Nov;92(5):1794-804; discussion 1804
references.pmid: 22051275
references.citation: J Invest Dermatol. 2013 Jan;133(1):181-90
references.pmid: 22895363
references.citation: Nature. 2001 Apr 26;410(6832):1111-6
references.pmid: 11323676
references.citation: Cancer Res. 1980 Oct;40(10):3502-7
references.pmid: 6108156
references.citation: Nat Genet. 2012 Oct;44(10):1104-10
references.pmid: 22941188
references.citation: Cancer Cell. 2003 Sep;4(3):181-9
references.pmid: 14522252
references.citation: Cancer Res. 2003 Nov 1;63(21):7042-6
references.pmid: 14612492
references.citation: Genesis. 2007 Aug;45(8):508-17
references.pmid: 17661398
references.citation: PLoS Genet. 2010 Sep 16;6(9):e1001120
references.pmid: 20862307
references.citation: Cancer Res. 1985 Dec;45(12 Pt 1):6024-33
references.pmid: 2998591
references.citation: Cancer Res. 1990 Sep 15;50(18):6068-74
references.pmid: 2168288
references.citation: J Thorac Dis. 2010 Sep;2(3):154-9
references.pmid: 22263037
references.citation: Nat Rev Cancer. 2009 Apr;9(4):265-73
references.pmid: 19262571
references.citation: Oncogene. 2001 Oct 4;20(45):6551-8
references.pmid: 11641780
references.citation: Int J Cancer. 2001 Feb 1;91(3):385-92
references.pmid: 11169964
references.citation: J Cell Biol. 2009 Oct 19;187(2):175-84
references.pmid: 19841136
references.citation: Virchows Arch A Pathol Anat Histol. 1980;387(3):251-7
references.pmid: 6779412
references.citation: J Invest Dermatol. 2004 Nov;123(5):973-81
references.pmid: 15482487
references.citation: Int J Cancer. 2013 Jan 1;132(1):9-18
references.pmid: 22618808
references.citation: Am J Pathol. 1996 Jan;148(1):63-9
references.pmid: 8546227
references.citation: Oncogene. 2011 Jan 13;30(2):127-38
references.pmid: 20890307
references.citation: Am J Pathol. 2011 Apr;178(4):1578-90
references.pmid: 21435445
references.citation: Sci Transl Med. 2011 Mar 23;3(75):75ra26
references.pmid: 21430269
references.citation: Lung Cancer. 2009 Jan;63(1):32-8
references.pmid: 18486272
references.citation: Pathobiology. 1992;60(3):136-42
references.pmid: 1320893
references.citation: N Engl J Med. 2006 Jul 13;355(2):213-5
references.pmid: 16837691
references.citation: Immunol Lett. 2009 Mar 24;123(1):31-7
references.pmid: 19428549
references.citation: Int J Urol. 2007 Nov;14(11):1034-9
references.pmid: 17956532