title: Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer.
abstract: Resistance to chemotherapy is a hallmark of pancreatic ductal adenocarcinoma (PDA) and has been partly attributed to the dense desmoplastic stroma, which forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a Ca2+-dependent enzyme, is secreted by PDA cells and cross-links proteins in the tumor microenvironment (TME) through acyl-transfer between glutamine and lysine residues, promoting PDA growth. The objective of the current study was to determine whether secreted TG2 by PDA cells alters the response of pancreatic tumors to gemcitabine. Orthotopic pancreatic xenografts and co-culture of PDA and stromal cells were employed to determine the mechanisms by which TG2 alters tumor-stroma interactions and response to gemcitabine. Analysis of the pancreatic The Cancer Genome Atlas (TCGA) database demonstrated that increased TG2 expression levels correlate with worse overall survival (hazard ratio=1.37). Stable TG2 knockdown in PDA cells led to decreased size of pancreatic xenografts and increased sensitivity to gemcitabine in vivo. However, TG2 downregulation did not increase cytotoxicity of gemcitabine in vitro. Additionally, multivessel density and gemcitabine uptake in pancreatic tumor tissue, as measured by mass spectrometry (MS-HPLC), were not significantly different in tumors expressing TG2 versus tumors in which TG2 was knocked down. Fibroblasts, stimulated by TG2 secreted by PDA cells, secrete laminin A1, which protects cancer cells from gemcitabine-induced cytotoxicity. In all, our results demonstrate that TG2 secreted in the pancreatic TME orchestrates the cross talk between cancer cells and stroma, impacting tumor growth and response to chemotherapy. Our study supports TG2 inhibition to increase the antitumor effects of gemcitabine in PDA.
authors: Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN.
authors: Jiyoon
authors: J
authors: Lee
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors: Bakhtiyor
authors: B
authors: Yakubov
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Cristina
authors: C
authors: Ivan
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors: David R
authors: DR
authors: Jones
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors: Andrea
authors: A
authors: Caperell-Grant
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors: Melissa
authors: M
authors: Fishel
authors: Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors: Horacio
authors: H
authors: Cardenas
authors: Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL; Robert H. Lurie Cancer Center, Chicago, IL; Jesse Brown VA Medical Center, Chicago, IL. Electronic address: daniela.matei@northwestern.edu.
authors: Daniela
authors: D
authors: Matei
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D007797:Laminin; D003841:Deoxycytidine; C084098:laminin A; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D000093542:Gemcitabine