title: Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution.
abstract: Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant "Gemcitabine-based chemotherapy" benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.|Present address: URBC-NARILIS, University of Namur, Namur, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Griveau
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Vindrieux
authors.affiliation: Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Belgium.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Maréchal
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Wiel
authors.affiliation: Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Saint-Antoine Hospital, Paris, France.|Sorbonne University, UPMC University, Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Svrcek
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Gout
authors.affiliation: Service de Biologie des Tumeurs, CHU de Bordeaux Hôpital du Haut Lévêque, Pessac, France.
authors.forename: Lamia
authors.initials: L
authors.lastname: Azzi
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.|Hospices Civils de Lyon, Université de Lyon, Lyon, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Payen
authors.affiliation: AP-HP, Hôpitaux Universitaires Paris Nord Val de Seine, Beaujon, France.|Paris Diderot University, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cros
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: de la Fouchardière
authors.affiliation: Service de Biologie des Tumeurs, CHU de Bordeaux Hôpital du Haut Lévêque, Pessac, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.affiliation: Université de Lyon, Lyon, France.|Hospices Civils de Lyon, Université de Lyon, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guitton
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
authors.affiliation: Sorbonne University, UPMC University and INSERM, UMRS 1147, Paris Descrates University, Paris, France.|Gastroenterology Department, APHP, Pitié Salpêtrière Hospital, Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Bachet
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Bernard
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004058:Diffusion; D019008:Drug Resistance, Neoplasm; D005260:Female; D024022:Fibrillar Collagens / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D024022:Fibrillar Collagens; D003841:Deoxycytidine; D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human; C119091:LOXL2 protein, human; D008249:Protein-Lysine 6-Oxidase; D000093542:Gemcitabine
keywords: biomarker; chemoresistance; collagen; lysyl oxidase; survival