title: Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma.
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.
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Fabienne
authors: F
authors: Guillaumond
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Ghislain
authors: G
authors: Bidaut
authors: INSERM, UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, F-13385 Marseille, France; Service de Chirurgie Digestive et Viscérale, F-13385 Marseille, France;
authors: Mehdi
authors: M
authors: Ouaissi
authors: INSERM, U1069, Laboratoire Nutrition, Croissance et Cancer, Université François Rabelais, F-37032 Tours, France;
authors: Stéphane
authors: S
authors: Servais
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Victoire
authors: V
authors: Gouirand
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Orianne
authors: O
authors: Olivares
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Sophie
authors: S
authors: Lac
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Laurence
authors: L
authors: Borge
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Julie
authors: J
authors: Roques
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Odile
authors: O
authors: Gayet
authors: INSERM, U1069, Laboratoire Nutrition, Croissance et Cancer, Université François Rabelais, F-37032 Tours, France;
authors: Michelle
authors: M
authors: Pinault
authors: INSERM, U1069, Laboratoire Nutrition, Croissance et Cancer, Université François Rabelais, F-37032 Tours, France;
authors: Cyrille
authors: C
authors: Guimaraes
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Jérémy
authors: J
authors: Nigri
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Céline
authors: C
authors: Loncle
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France; Service Hospitalier d'Anatomie et Cytologie Pathologiques Humaines, Assistance Publique-Hôpitaux de Marseille, F-13015 Marseille, France;
authors: Marie-Noëlle
authors: MN
authors: Lavaut
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France; Service Hospitalier d'Anatomie et Cytologie Pathologiques Humaines, Assistance Publique-Hôpitaux de Marseille, F-13015 Marseille, France;
authors: Stéphane
authors: S
authors: Garcia
authors: European Genomic Institute for Diabetes, FR 3508, Université Lille 2, INSERM, U1011, and Institut Pasteur de Lille, F-59019 Lille, France; and.
authors: Anne
authors: A
authors: Tailleux
authors: European Genomic Institute for Diabetes, FR 3508, Université Lille 2, INSERM, U1011, and Institut Pasteur de Lille, F-59019 Lille, France; and.
authors: Bart
authors: B
authors: Staels
authors: Molecular Endocrinology and Oncology Research Center, Quebec, QC, Canada G1V 4G2.
authors: Ezequiel
authors: E
authors: Calvo
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Richard
authors: R
authors: Tomasini
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
authors: Juan Lucio
authors: JL
authors: Iovanna
authors: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France; sophie.vasseur@inserm.fr.
authors: Sophie
authors: S
authors: Vasseur
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D002999:Clone Cells; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D008074:Lipoproteins; D011973:Receptors, LDL; D003841:Deoxycytidine; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; D000093542:Gemcitabine
keywords: LDLR; cholesterol; gemcitabine; metabolism; pancreatic cancer