title: The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling.
abstract: Pancreatic cancer, one of the deadliest human malignancies, is almost uniformly associated with a mutant, constitutively active form of the oncogene Kras. Studies in genetically engineered mouse models have defined a requirement for oncogenic KRAS in both the formation of pancreatic intraepithelial neoplasias, the most common precursor lesions to pancreatic cancer, and in the maintenance and progression of these lesions. Previous work using an inducible model allowing tissue-specific and reversible expression of oncogenic Kras in the pancreas indicates that inactivation of this GTPase at the pancreatic intraepithelial neoplasia stage promotes pancreatic tissue repair. Here, we extend these findings to identify GLI1, a transcriptional effector of the Hedgehog pathway, as a central player in pancreatic tissue repair upon Kras inactivation. Deletion of a single allele of Gli1 results in improper stromal remodeling and perdurance of the inflammatory infiltrate characteristic of pancreatic tumorigenesis. Strikingly, this partial loss of Gli1 affects activated fibroblasts in the pancreas and the recruitment of immune cells that are vital for tissue recovery. Analysis of the mechanism using expression and chromatin immunoprecipitation assays identified a subset of cytokines, including IL-6, mIL-8, Mcp-1, and M-csf (Csf1), as direct GLI1 target genes potentially mediating this phenomenon. Finally, we demonstrate that canonical Hedgehog signaling, a known regulator of Gli1 activity, is required for pancreas recovery. Collectively, these data delineate a new pathway controlling tissue repair and highlight the importance of GLI1 in regulation of the pancreatic microenvironment during this cellular process.
authors.affiliation: From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Esha
authors.initials: E
authors.lastname: Mathew
authors.affiliation: From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Collins
authors.affiliation: the Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.affiliation: From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, the Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan 48109, Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Holtz
authors.affiliation: the Department of Pathology, Michigan Center for Translational Pathology, and.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Departments of Surgery, and.
authors.forename: James O
authors.initials: JO
authors.lastname: Hogan
authors.affiliation: Departments of Surgery, and.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Tata
authors.affiliation: From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Allen
authors.affiliation: the Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, the Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan 48109, Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109 Departments of Surgery, and marinapa@umich.edu.
authors.forename: Marina Pasca
authors.initials: MP
authors.lastname: di Magliano
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology* / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
keywords: Cytokine; Fibroblast; Hedgehog Signaling Pathway; Inflammation; Macrophage; Pancreas; Pancreatic Cancer
references.citation: Int J Cancer. 2004 Jan 10;108(2):173-80
references.pmid: 14639599
references.citation: Nat Commun. 2013;4:1886
references.pmid: 23695680
references.citation: PLoS One. 2013;8(3):e58935
references.pmid: 23520544
references.citation: PLoS One. 2010 Feb 18;5(2):e9304
references.pmid: 20174584
references.citation: Gastroenterology. 2012 Apr;142(4):730-733.e9
references.pmid: 22226782
references.citation: Nature. 2003 Oct 23;425(6960):851-6
references.pmid: 14520413
references.citation: Genes Dev. 2006 May 15;20(10):1218-49
references.pmid: 16702400
references.citation: N Engl J Med. 1993 May 20;328(20):1433-7
references.pmid: 8479461
references.citation: Genes Dev. 1998 Jun 1;12(11):1705-13
references.pmid: 9620856
references.citation: Trends Immunol. 2001 Apr;22(4):199-204
references.pmid: 11274925
references.citation: Cancer Res. 2006 Jan 1;66(1):95-106
references.pmid: 16397221
references.citation: Trends Cell Biol. 2005 Nov;15(11):599-607
references.pmid: 16202600
references.citation: Gastroenterology. 2008 Aug;135(2):621-31
references.pmid: 18515092
references.citation: Nucleic Acids Res. 2005 Mar 22;33(5):e51
references.pmid: 15784609
references.citation: Am J Pathol. 2010 Mar;176(3):1241-55
references.pmid: 20110414
references.citation: PLoS One. 2011;6(11):e27725
references.pmid: 22140463
references.citation: Am J Surg Pathol. 2001 May;25(5):579-86
references.pmid: 11342768
references.citation: Ann N Y Acad Sci. 2010 Feb;1188:143-52
references.pmid: 20201897
references.citation: Nat Genet. 2002 Sep;32(1):128-34
references.pmid: 12185368
references.citation: Genes Dev. 1998 Jun 1;12(11):1691-704
references.pmid: 9620855
references.citation: Mol Cell Biol. 2009 Nov;29(22):6074-85
references.pmid: 19703992
references.citation: Development. 2000 Apr;127(8):1593-605
references.pmid: 10725236
references.citation: Gastroenterology. 2000 Jul;119(1):211-9
references.pmid: 10889171
references.citation: Am J Physiol. 1985 Dec;249(6 Pt 1):G702-10
references.pmid: 2417493
references.citation: J Clin Invest. 2012 Feb;122(2):639-53
references.pmid: 22232209
references.citation: Annu Rev Cell Dev Biol. 2011;27:513-37
references.pmid: 21801010
references.citation: J Biol Chem. 2013 Apr 26;288(17):11786-94
references.pmid: 23482563
references.citation: Cancer Cell. 2007 Mar;11(3):291-302
references.pmid: 17349585
references.citation: Nat Rev Immunol. 2011 Oct 14;11(11):723-37
references.pmid: 21997792
references.citation: J Clin Invest. 2010 Feb;120(2):508-20
references.pmid: 20071774
references.citation: Cancer Res. 2007 Sep 1;67(17):8121-30
references.pmid: 17804724
references.citation: Genes Dev. 2006 Nov 15;20(22):3161-73
references.pmid: 17114586
references.citation: Cancer Cell. 2011 Jun 14;19(6):728-39
references.pmid: 21665147
references.citation: PLoS One. 2012;7(12):e49707
references.pmid: 23226501
references.citation: J Clin Invest. 2009 Dec;119(12):3713-22
references.pmid: 19884654
references.citation: J Clin Invest. 2005 Jan;115(1):56-65
references.pmid: 15630444
references.citation: Development. 2002 Oct;129(20):4753-61
references.pmid: 12361967
references.citation: Nature. 2012 Nov 15;491(7424):399-405
references.pmid: 23103869
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14071-6
references.pmid: 12391318
references.citation: Cell Prolif. 2000 Jun;33(3):167-87
references.pmid: 10959625
references.citation: Genes Dev. 2003 Dec 15;17(24):3112-26
references.pmid: 14681207
references.citation: Cancer Res. 2007 Oct 1;67(19):9518-27
references.pmid: 17909062
references.citation: Genes Dev. 2009 Jan 1;23(1):24-36
references.pmid: 19136624
references.citation: Gastroenterology. 2005 Mar;128(3):728-41
references.pmid: 15765408
references.citation: Nature. 2011 Apr 7;472(7341):110-4
references.pmid: 21389986
references.citation: J Biol Chem. 2013 Jul 19;288(29):21389-21398
references.pmid: 23740243
references.citation: Cancer Cell. 2003 Dec;4(6):437-50
references.pmid: 14706336
references.citation: Science. 2008 Sep 26;321(5897):1801-6
references.pmid: 18772397
references.citation: Genes Dev. 2001 Dec 15;15(24):3249-62
references.pmid: 11751631
references.citation: Gut. 2012 Mar;61(3):449-58
references.pmid: 21730103
references.citation: Curr Top Dev Biol. 2003;53:1-114
references.pmid: 12509125
references.citation: PLoS Med. 2008 Dec 9;5(12):e239
references.pmid: 19071955