Author:
Guillaumond Fabienne,Bidaut Ghislain,Ouaissi Mehdi,Servais Stéphane,Gouirand Victoire,Olivares Orianne,Lac Sophie,Borge Laurence,Roques Julie,Gayet Odile,Pinault Michelle,Guimaraes Cyrille,Nigri Jérémy,Loncle Céline,Lavaut Marie-Noëlle,Garcia Stéphane,Tailleux Anne,Staels Bart,Calvo Ezequiel,Tomasini Richard,Iovanna Juan Lucio,Vasseur Sophie
Abstract
The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse.
Publisher
Proceedings of the National Academy of Sciences
Cited by
301 articles.
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