title: Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression.
abstract: OBJECTIVE
  Aggressive pancreatic cancer is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. The objective of the study was to determine the functions of tissue transglutaminase (TG2), a Ca(2+)-dependent enzyme that cross-links proteins through transamidation and is abundantly expressed by pancreatic cancer cells in the pancreatic stroma.
  
  
  METHODS
  Orthotopic pancreatic xenografts and coculture systems tested the mechanisms by which the enzyme modulates tumor-stroma interactions.
  
  
  RESULTS
  We show that TG2 secreted by cancer cells effectively molds the stroma by cross-linking collagen, which, in turn, activates fibroblasts and stimulates their proliferation. The stiff fibrotic stromal reaction conveys mechanical cues to cancer cells, leading to activation of the YAP/TAZ transcription factors, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells leads to decreased size of pancreatic xenografts.
  
  
  CONCLUSIONS
  Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the cross-talk between cancer cells and stroma fundamentally affecting tumor growth. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Condello
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Bakhtiyor
authors.initials: B
authors.lastname: Yakubov
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Robert
authors.initials: R
authors.lastname: Emerson
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caperell-Grant
authors.affiliation: Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Hitomi
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Jingwu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana. Richard L. Roudebush VA Medical Center, Indianapolis, Indiana. dmatei@iu.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
mesh_terms: D000217:Acyltransferases; D000818:Animals; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D014157:Transcription Factors; D003094:Collagen; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins