title: PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion.
abstract: Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis.
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Bonastre
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Verdura
authors.affiliation: MRC-Holland, Willem Schoutenstraat, the Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Zondervan
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Facchinetti
authors.affiliation: Department of Pathology, Institut Albert Bonniot, INSERM U823, University Joseph Fourier, CHU, Grenoble Hôpital Michallon, Grenoble, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
authors.affiliation: Department of Otolaryngology of the Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Chiara
authors.affiliation: Department of Otolaryngology of the Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rodrigo
authors.affiliation: Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.affiliation: Pathology Department, Bellvitge Hospital, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Condom
authors.affiliation: Pathology Department, Bellvitge Hospital, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Agustin
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Departments of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
authors.affiliation: Department of Pathology, Institut Albert Bonniot, INSERM U823, University Joseph Fourier, CHU, Grenoble Hôpital Michallon, Grenoble, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: MRC-Holland, Willem Schoutenstraat, the Netherlands.
authors.forename: Suvi
authors.initials: S
authors.lastname: Savola
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. mscespedes@idibell.cat.
authors.forename: Montse
authors.initials: M
authors.lastname: Sanchez-Cespedes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000556:secondary; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011493:Protein Kinase C / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D059467:Transcriptome; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; C107953:RAC1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein
references.citation: Nature. 2008 Oct 23;455(7216):1069-75
references.pmid: 18948947
references.citation: Oncogene. 2008 Nov 24;27(55):6878-87
references.pmid: 19029931
references.citation: Clin Transl Oncol. 2009 May;11(5):263-9
references.pmid: 19451058
references.citation: Oncogene. 2007 Dec 13;26(57):7825-32
references.pmid: 17599048
references.citation: Dev Cell. 2008 Feb;14(2):205-15
references.pmid: 18267089
references.citation: Hum Mutat. 2008 May;29(5):617-22
references.pmid: 18386774
references.citation: Cancer Res. 2002 Jul 1;62(13):3659-62
references.pmid: 12097271
references.citation: Oncogene. 2003 Jun 5;22(23):3608-15
references.pmid: 12789269
references.citation: Curr Biol. 2003 Aug 5;13(15):1330-4
references.pmid: 12906794
references.citation: J Biol Chem. 2003 Aug 15;278(33):31240-50
references.pmid: 12756256
references.citation: Oncogene. 2004 Apr 8;23(15):2600-16
references.pmid: 15007380
references.citation: Genomics. 2004 Jun;83(6):970-9
references.pmid: 15177551
references.citation: Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3
references.pmid: 5279523
references.citation: Cell. 1988 Feb 12;52(3):311-20
references.pmid: 3345562
references.citation: Anticancer Res. 1993 May-Jun;13(3):627-30
references.pmid: 8391244
references.citation: Hum Mutat. 2009 Aug;30(8):1199-206
references.pmid: 19472407
references.citation: Nat Genet. 2009 Nov;41(11):1238-42
references.pmid: 19801978
references.citation: Cancer Res. 2010 Mar 15;70(6):2158-64
references.pmid: 20215515
references.citation: J Cell Sci. 2010 Apr 1;123(Pt 7):1089-98
references.pmid: 20197404
references.citation: J Pathol. 2010 Sep;222(1):89-98
references.pmid: 20556744
references.citation: Sci Transl Med. 2010 Dec 15;2(62):62ra93
references.pmid: 21160078
references.citation: Nat Cell Biol. 2011 Jan;13(1):49-58
references.pmid: 21170030
references.citation: Clin Microbiol Rev. 2011 Jan;24(1):210-29
references.pmid: 21233513
references.citation: FEBS Lett. 2011 Apr 6;585(7):944-51
references.pmid: 21192934
references.citation: Exp Cell Res. 2011 Aug 1;317(13):1787-95
references.pmid: 21619876
references.citation: Trends Cell Biol. 2011 Jul;21(7):401-8
references.pmid: 21530265
references.citation: Nat Cell Biol. 2011 Jul;13(7):860-6
references.pmid: 21685893
references.citation: Nat Rev Cancer. 2012 Jan;12(1):23-38
references.pmid: 22169974
references.citation: Gut. 2012 Feb;61(2):220-8
references.pmid: 21865402
references.citation: N Engl J Med. 2012 May 17;366(20):1905-13
references.pmid: 22591296
references.citation: Cancer Discov. 2011 Jun;1(1):78-89
references.pmid: 22328973
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):E2361-70
references.pmid: 22891351
references.citation: Cancer Cell. 2012 Sep 11;22(3):389-403
references.pmid: 22975380
references.citation: Nature. 2012 Sep 27;489(7417):519-25
references.pmid: 22960745
references.citation: Cancer Cell. 2012 Nov 13;22(5):601-14
references.pmid: 23153534
references.citation: Int J Cancer. 2014 Mar 1;134(5):1045-54
references.pmid: 23959540
references.citation: Genes Chromosomes Cancer. 1998 Jul;22(3):232-40
references.pmid: 9624535
references.citation: Cell. 1994 Sep 9;78(5):761-71
references.pmid: 8087844
references.citation: Cancer Res. 2014 Nov 1;74(21):5978-88
references.pmid: 25217522
references.citation: J Natl Cancer Inst. 1998 Jul 1;90(13):972-7
references.pmid: 9665144
references.citation: Nat Cell Biol. 2005 Mar;7(3):262-9
references.pmid: 15723052
references.citation: Mol Biol Cell. 2006 Jun;17(6):2839-52
references.pmid: 16611743
references.citation: Curr Biol. 2007 Oct 9;17(19):1623-34
references.pmid: 17825562
references.citation: Dev Cell. 2007 Nov;13(5):609-22
references.pmid: 17981131
references.citation: Nat Cell Biol. 2000 Aug;2(8):540-7
references.pmid: 10934475
references.citation: Science. 2000 Oct 6;290(5489):144-7
references.pmid: 11021801