Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer

Jiyoon Lee, Bakhtiyor Yakubov, Cristina Ivan, David R. Jones, Andrea Caperell-Grant, Melissa Fishel, Horacio Cardenas, Daniela Matei

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)689-698
Number of pages10
JournalNeoplasia (United States)
Volume18
Issue number11
DOIs
StatePublished - 2016

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gemcitabine
Pancreatic Neoplasms
Adenocarcinoma
Neoplasms
Tumor Microenvironment
Heterografts
Cancer-Associated Fibroblasts
transglutaminase 2
Drug Therapy
Atlases
Laminin
Stromal Cells
Growth
Coculture Techniques
Glutamine

ASJC Scopus subject areas

  • Cancer Research

Cite this

Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer. / Lee, Jiyoon; Yakubov, Bakhtiyor; Ivan, Cristina; Jones, David R.; Caperell-Grant, Andrea; Fishel, Melissa; Cardenas, Horacio; Matei, Daniela.

In: Neoplasia (United States), Vol. 18, No. 11, 2016, p. 689-698.

Research output: Contribution to journalArticle

Lee, Jiyoon ; Yakubov, Bakhtiyor ; Ivan, Cristina ; Jones, David R. ; Caperell-Grant, Andrea ; Fishel, Melissa ; Cardenas, Horacio ; Matei, Daniela. / Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer. In: Neoplasia (United States). 2016 ; Vol. 18, No. 11. pp. 689-698.
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AU - Lee, Jiyoon

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AU - Ivan, Cristina

AU - Jones, David R.

AU - Caperell-Grant, Andrea

AU - Fishel, Melissa

AU - Cardenas, Horacio

AU - Matei, Daniela

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AB - 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.

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