title: Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2.
abstract: One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagen-rich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP-dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP in the collagen microenvironment increases ERK1/2 phosphorylation and HMGA2 expression, and thereby further attenuates gemcitabine-induced checkpoint arrest. MT1-MMP also allows PDAC cells to continue to proliferate in the presence of gemcitabine in a xenograft mouse model. Clinically, human tumors with increased MT1-MMP show increased HMGA2 expression. Overall, our data show that collagen upregulation of MT1-MMP contributes to gemcitabine resistance in vitro and in a xenograft mouse model, and suggest that targeting MT1-MMP could be a novel approach to sensitize pancreatic tumors to gemcitabine.
authors.affiliation: Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-dangi-garimella@northwestern.edu
authors.forename: Surabhi
authors.initials: S
authors.lastname: Dangi-Garimella
authors.forename: Seth B
authors.initials: SB
authors.lastname: Krantz
authors.forename: Morgan R
authors.initials: MR
authors.lastname: Barron
authors.forename: Mario A
authors.initials: MA
authors.lastname: Shields
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Heiferman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000737:chemistry*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D025743:HMGA2 Protein / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D024042:Collagen Type I; D025743:HMGA2 Protein; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D000093542:Gemcitabine