Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution

Benjamin Le Calvé, Audrey Griveau, David Vindrieux, Raphaël Maréchal, Clotilde Wiel, Magali Svrcek, Johann Gout, Lamia Azzi, Léa Payen, Jérôme Cros, Christelle de la Fouchardière, Pierre Dubus, Jérôme Guitton, Laurent Bartholin, Jean-Baptiste Bachet, David Bernard

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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.

langue originaleAnglais
Pages (de - à)32100-12
Nombre de pages13
journalOncotarget
Volume7
Numéro de publication22
Les DOIs
étatPublié - 2016
Modification externeOui

Empreinte digitale

Protein-Lysine 6-Oxidase
Adenocarcinoma
gemcitabine
Drug Therapy
Pharmaceutical Preparations
Fibrillar Collagens
Neoplasms
Extracellular Matrix
Biomarkers
Collagen

Citer ceci

Le Calvé, Benjamin ; Griveau, Audrey ; Vindrieux, David ; Maréchal, Raphaël ; Wiel, Clotilde ; Svrcek, Magali ; Gout, Johann ; Azzi, Lamia ; Payen, Léa ; Cros, Jérôme ; de la Fouchardière, Christelle ; Dubus, Pierre ; Guitton, Jérôme ; Bartholin, Laurent ; Bachet, Jean-Baptiste ; Bernard, David. / Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution. Dans: Oncotarget. 2016 ; Vol 7, Numéro 22. p. 32100-12.
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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.",
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author = "{Le Calv{\'e}}, Benjamin and Audrey Griveau and David Vindrieux and Rapha{\"e}l Mar{\'e}chal and Clotilde Wiel and Magali Svrcek and Johann Gout and Lamia Azzi and L{\'e}a Payen and J{\'e}r{\^o}me Cros and {de la Fouchardi{\`e}re}, Christelle and Pierre Dubus and J{\'e}r{\^o}me Guitton and Laurent Bartholin and Jean-Baptiste Bachet and David Bernard",
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Le Calvé, B, Griveau, A, Vindrieux, D, Maréchal, R, Wiel, C, Svrcek, M, Gout, J, Azzi, L, Payen, L, Cros, J, de la Fouchardière, C, Dubus, P, Guitton, J, Bartholin, L, Bachet, J-B & Bernard, D 2016, 'Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution', Oncotarget, VOL. 7, Numéro 22, p. 32100-12. https://doi.org/10.18632/oncotarget.8527

Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution. / Le Calvé, Benjamin; Griveau, Audrey; Vindrieux, David; Maréchal, Raphaël; Wiel, Clotilde; Svrcek, Magali; Gout, Johann; Azzi, Lamia; Payen, Léa; Cros, Jérôme; de la Fouchardière, Christelle; Dubus, Pierre; Guitton, Jérôme; Bartholin, Laurent; Bachet, Jean-Baptiste; Bernard, David.

Dans: Oncotarget, Vol 7, Numéro 22, 2016, p. 32100-12.

Résultats de recherche: Contribution à un journal/une revueArticle

TY - JOUR

T1 - Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution

AU - Le Calvé, Benjamin

AU - Griveau, Audrey

AU - Vindrieux, David

AU - Maréchal, Raphaël

AU - Wiel, Clotilde

AU - Svrcek, Magali

AU - Gout, Johann

AU - Azzi, Lamia

AU - Payen, Léa

AU - Cros, Jérôme

AU - de la Fouchardière, Christelle

AU - Dubus, Pierre

AU - Guitton, Jérôme

AU - Bartholin, Laurent

AU - Bachet, Jean-Baptiste

AU - Bernard, David

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.18632/oncotarget.8527

DO - 10.18632/oncotarget.8527

M3 - Article

C2 - 27050073

VL - 7

SP - 32100

EP - 32112

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 22

ER -