Transforming growth factor-β limits secretion of lumican by activated stellate cells within primary pancreatic adenocarcinoma tumors

Ya'An Kang, David Roife, Yeonju Lee, Hailong Lv, Rei Suzuki, Jianhua Ling, Mayrim V. Rios Perez, Xinqun Li, Bingbing Dai, Michael Pratt, Mark J. Truty, Deyali Chatterjee, Huamin Wang, Ryan M. Thomas, Yu Wang, Eugene J. Koay, Paul J. Chiao, Matthew H. Katz, Jason B. Fleming

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC. Experimental Design: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment. Results: Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-β, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen. Conclusions: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 22(19); 4934-46.

Original languageEnglish (US)
Pages (from-to)4934-4946
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number19
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kang, YA., Roife, D., Lee, Y., Lv, H., Suzuki, R., Ling, J., Rios Perez, M. V., Li, X., Dai, B., Pratt, M., Truty, M. J., Chatterjee, D., Wang, H., Thomas, R. M., Wang, Y., Koay, E. J., Chiao, P. J., Katz, M. H., & Fleming, J. B. (2016). Transforming growth factor-β limits secretion of lumican by activated stellate cells within primary pancreatic adenocarcinoma tumors. Clinical Cancer Research, 22(19), 4934-4946. https://doi.org/10.1158/1078-0432.CCR-15-2780