Transforming growth factor beta‐induced, an extracellular matrix interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration. Issue 6 (28th March 2019)

• Record Type: Journal Article
• Authors: Costanza, Brunella; Rademaker, Gilles; Tiamiou, Assia; De Tullio, Pascal; Leenders, Justine; Blomme, Arnaud; Bellier, Justine; Bianchi, Elettra; Turtoi, Andrei; Delvenne, Philippe; Bellahcène, Akeila; Peulen, Olivier; Castronovo, Vincent
• Is Part Of: International journal of cancer. Volume 145:Issue 6(2019)
• Page Start: 1570
• Page End: 1584
• Publication Date: 2019-03-28
• Subjects: pancreas -- TGFBI -- integrin -- extracellular matrix -- glycolysis; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32247
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy with no efficient therapy available up‐to‐date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high transforming growth factor beta‐induced (TGFBI) expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates focal adhesion kinase signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic extracellular matrix interacting protein that bears the potential to serve as a target for new anti‐PDAC therapeutic strategies. Abstract : What's new? While pancreatic ductal adenocarcinoma (PDAC) continues to have exceedingly low 5‐year survival rates, there is hope that the discovery of reliable biomarkers and therapeutic targets can improve early diagnosis and treatment outcomes. To that end, the authors of this study identify the extracellular matrix protein transforming growth factor beta‐induced (TGFBI) as a promising PDAC target. In PDAC patients, high TGFBI expression was associated with poor outcome. In PDAC cells, tumor aggressiveness was associated with greater TGFBI synthesis and secretion. Mechanistic analyses show that TGFBI activates FAK signaling via integrin αVβ5 binding, enhancing glycolysis and invasiveness in PDAC cells.