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Pancreatic Neoplasms: HELP
Articles by Celine Loncle
Based on 17 articles published since 2010
(Why 17 articles?)
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Between 2010 and 2020, C. Loncle wrote the following 17 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts. 2017

Nicolle, Rémy / Blum, Yuna / Marisa, Laetitia / Loncle, Celine / Gayet, Odile / Moutardier, Vincent / Turrini, Olivier / Giovannini, Marc / Bian, Benjamin / Bigonnet, Martin / Rubis, Marion / Elarouci, Nabila / Armenoult, Lucile / Ayadi, Mira / Duconseil, Pauline / Gasmi, Mohamed / Ouaissi, Mehdi / Maignan, Aurélie / Lomberk, Gwen / Boher, Jean-Marie / Ewald, Jacques / Bories, Erwan / Garnier, Jonathan / Goncalves, Anthony / Poizat, Flora / Raoul, Jean-Luc / Secq, Veronique / Garcia, Stephane / Grandval, Philippe / Barraud-Blanc, Marine / Norguet, Emmanuelle / Gilabert, Marine / Delpero, Jean-Robert / Roques, Julie / Calvo, Ezequiel / Guillaumond, Fabienne / Vasseur, Sophie / Urrutia, Raul / de Reyniès, Aurélien / Dusetti, Nelson / Iovanna, Juan. ·Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France. Electronic address: remy.nicolle@ligue-cancer.net. · Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France. · Hôpital Nord, Marseille, France; Aix Marseille Université, Marseille, France. · Aix Marseille Université, Marseille, France; Institut Paoli-Calmettes, Marseille, France. · Institut Paoli-Calmettes, Marseille, France. · Hôpital Nord, Marseille, France. · Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. · Aix Marseille Université, Marseille, France; Hôpital de la Timone, Marseille, France. · Hôpital de la Timone, Marseille, France. · Centre Génomique du Centre de Recherche du CHUL Research Center, Ville de Québec, QC, Canada. · Division of Research, Department of Surgery, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France. Electronic address: juan.iovanna@inserm.fr. ·Cell Rep · Pubmed #29186684.

ABSTRACT: Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

2 Article Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts. 2017

Bian, Benjamin / Bigonnet, Martin / Gayet, Odile / Loncle, Celine / Maignan, Aurélie / Gilabert, Marine / Moutardier, Vincent / Garcia, Stephane / Turrini, Olivier / Delpero, Jean-Robert / Giovannini, Marc / Grandval, Philippe / Gasmi, Mohamed / Ouaissi, Mehdi / Secq, Veronique / Poizat, Flora / Nicolle, Rémy / Blum, Yuna / Marisa, Laetitia / Rubis, Marion / Raoul, Jean-Luc / Bradner, James E / Qi, Jun / Lomberk, Gwen / Urrutia, Raul / Saul, Andres / Dusetti, Nelson / Iovanna, Juan. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France. · Hôpital Nord, Marseille, France. · CIC1409, AP-HM-Hôpital Nord, Aix-Marseille Université, Marseille, France. · Institut Paoli-Calmettes, Marseille, France. · Hôpital de la Timone, Marseille, France. · Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. · Laboratory of Epigenetics and Chromatin Dynamics, Departments of Biochemistry and Molecular Biology and Medicine, Mayo Clinic, Rochester, MN, USA. · Centre Interdisciplinaire de Nanoscience de Marseille-CNRS UMR 7325, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France nelson.dusetti@inserm.fr juan.iovanna@inserm.fr. ·EMBO Mol Med · Pubmed #28275007.

ABSTRACT:

3 Article Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. 2016

Leca, Julie / Martinez, Sébastien / Lac, Sophie / Nigri, Jérémy / Secq, Véronique / Rubis, Marion / Bressy, Christian / Sergé, Arnauld / Lavaut, Marie-Noelle / Dusetti, Nelson / Loncle, Céline / Roques, Julie / Pietrasz, Daniel / Bousquet, Corinne / Garcia, Stéphane / Granjeaud, Samuel / Ouaissi, Mehdi / Bachet, Jean Baptiste / Brun, Christine / Iovanna, Juan L / Zimmermann, Pascale / Vasseur, Sophie / Tomasini, Richard. · ·J Clin Invest · Pubmed #27701147.

ABSTRACT: The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell-mediated uptake of CAF-derived ANXA6+ EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6+ EVs enhanced tumorigenesis. We found that the presence of ANXA6+ EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF-tumor cell crosstalk supported by ANXA6+ EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA.

4 Article A pancreatic ductal adenocarcinoma subpopulation is sensitive to FK866, an inhibitor of NAMPT. 2016

Barraud, Marine / Garnier, Jonathan / Loncle, Celine / Gayet, Odile / Lequeue, Charlotte / Vasseur, Sophie / Bian, Benjamin / Duconseil, Pauline / Gilabert, Marine / Bigonnet, Martin / Maignan, Aurélie / Moutardier, Vincent / Garcia, Stephane / Turrini, Olivier / Delpero, Jean-Robert / Giovannini, Marc / Grandval, Philippe / Gasmi, Mohamed / Ouaissi, Mehdi / Secq, Veronique / Poizat, Flora / Guibert, Nicolas / Iovanna, Juan / Dusetti, Nelson. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Hôpital Nord, Marseille, France. · CIC1409, AP-HM - Nord University Hospital, Aix-Marseille University, Marseille, France. · Institut Paoli-Calmettes, Marseille, France. · Hôpital de la Timone, Marseille, France. · Hospices Civils de Lyon, Lyon, France. ·Oncotarget · Pubmed #27462772.

ABSTRACT: Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866.

5 Article The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation. 2016

Loncle, C / Molejon, M I / Lac, S / Tellechea, J I / Lomberk, G / Gramatica, L / Fernandez Zapico, M F / Dusetti, N / Urrutia, R / Iovanna, J L. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, USA. · Department of Surgery, University of Cordoba, Cordoba, Argentine. · Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, USA. ·Cell Death Dis · Pubmed #27415425.

ABSTRACT: Both clinical and experimental evidence have firmly established that chronic pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane protein 1 (VMP1), a pancreatitis-associated protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.

6 Article Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation. 2015

Grasso, Daniel / Bintz, Jennifer / Lomberk, Gwen / Molejon, Maria Ines / Loncle, Celine / Garcia, Maria Noé / Lopez, Maria Belen / Urrutia, Raul / Iovanna, Juan L. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, USA. ·Sci Rep · Pubmed #26617245.

ABSTRACT: Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.

7 Article IL17 Functions through the Novel REG3β-JAK2-STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer. 2015

Loncle, Celine / Bonjoch, Laia / Folch-Puy, Emma / Lopez-Millan, Maria Belen / Lac, Sophie / Molejon, Maria Inés / Chuluyan, Eduardo / Cordelier, Pierre / Dubus, Pierre / Lomberk, Gwen / Urrutia, Raul / Closa, Daniel / Iovanna, Juan L. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Experimental Pathology Department, IIBB-CSIC-IDIBAPS, Barcelona, Spain. · Laboratory of Immunomodulators, School of Medicine, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)-University of Buenos Aires, Buenos Aires, Argentina. · INSERM UMR U1037, Centre de Recherche sur le Cancer de Toulouse, CHU Rangueil, Toulouse, France. · EA2406, Histologie et pathologie moléculaire des tumeurs, Université de Bordeaux, Bordeaux, France. · Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, New York. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. juan.iovanna@inserm.fr. ·Cancer Res · Pubmed #26404002.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering "druggable" molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3β during pancreatitis and PDAC initiation.

8 Article Deciphering the cellular source of tumor relapse identifies CD44 as a major therapeutic target in pancreatic adenocarcinoma. 2015

Molejon, Maria Inés / Tellechea, Juan Ignacio / Loncle, Celine / Gayet, Odile / Gilabert, Marine / Duconseil, Pauline / Lopez-Millan, Maria Belen / Moutardier, Vincent / Gasmi, Mohamed / Garcia, Stephane / Turrini, Olivier / Ouaissi, Mehdi / Poizat, Flora / Dusetti, Nelson / Iovanna, Juan. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Hôpital Nord, Marseille, France. · Institut Paoli-Calmettes, Marseille, France. · Hôpital de la Timone, Marseille, France. ·Oncotarget · Pubmed #25797268.

ABSTRACT: It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC.

9 Article Transcriptomic analysis predicts survival and sensitivity to anticancer drugs of patients with a pancreatic adenocarcinoma. 2015

Duconseil, Pauline / Gilabert, Marine / Gayet, Odile / Loncle, Celine / Moutardier, Vincent / Turrini, Olivier / Calvo, Ezequiel / Ewald, Jacques / Giovannini, Marc / Gasmi, Mohamed / Bories, Erwan / Barthet, Marc / Ouaissi, Mehdi / Goncalves, Anthony / Poizat, Flora / Raoul, Jean Luc / Secq, Veronique / Garcia, Stephane / Viens, Patrice / Iovanna, Juan / Dusetti, Nelson. ·Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France. · Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France; Department of Surgery, Hôpital Nord, Marseille, France. · Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France; Paoli-Calmettes Institute, Marseille, France. · Genomic Center, CHUL Research Centre, Quebec City, Quebec, Canada. · Paoli-Calmettes Institute, Marseille, France. · Department of Gastroenterology, Hôpital Nord, Marseille, France. · Department of Surgery, La Timone Hospital, Marseille, France. · Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France. Electronic address: juan.iovanna@inserm.fr. · Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France. Electronic address: nelson.dusetti@inserm.fr. ·Am J Pathol · Pubmed #25765988.

ABSTRACT: A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is the molecular heterogeneity of this disease, which is reflected in an equally diverse pattern of clinical outcome and in responses to therapies. We developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by endoscopic ultrasound-guided fine-needle aspiration or surgery and were preserved as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of these data was able to discriminate between patients with long- and short-term survival corresponding to patients with moderately or poorly differentiated PDAC tumors, respectively. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro using a chemogram, similar to the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient dependent. We also found that transcriptomic analysis predicts the sensitivity of cells to the five anticancer drugs most frequently used to treat patients with PDAC. In conclusion, using this approach, we found that transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC.

10 Article Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. 2015

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. ·INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France; · INSERM, UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, F-13385 Marseille, France; Service de Chirurgie Digestive et Viscérale, F-13385 Marseille, France; · INSERM, U1069, Laboratoire Nutrition, Croissance et Cancer, Université François Rabelais, F-37032 Tours, France; · 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; · European Genomic Institute for Diabetes, FR 3508, Université Lille 2, INSERM, U1011, and Institut Pasteur de Lille, F-59019 Lille, France; and. · Molecular Endocrinology and Oncology Research Center, Quebec, QC, Canada G1V 4G2. · 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. ·Proc Natl Acad Sci U S A · Pubmed #25675507.

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.

11 Article A subgroup of pancreatic adenocarcinoma is sensitive to the 5-aza-dC DNA methyltransferase inhibitor. 2015

Gayet, Odile / Loncle, Celine / Duconseil, Pauline / Gilabert, Marine / Lopez, Maria Belen / Moutardier, Vincent / Turrini, Olivier / Calvo, Ezequiel / Ewald, Jacques / Giovannini, Marc / Gasmi, Mohamed / Bories, Erwan / Barthet, Marc / Ouaissi, Mehdi / Goncalves, Anthony / Poizat, Flora / Raoul, Jean Luc / Secq, Veronique / Garcia, Stephane / Viens, Patrice / Dusetti, Nelson / Iovanna, Juan. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Hôpital Nord, Marseille, France. · Institut Paoli-Calmettes, Marseille, France. · Centre Génomique du Centre de recherche du CHUL Research Center, Quebec, Canada. · Hôpital Nord, Département de Gastroentérologie, Marseille, France. · Hôpital de la Timone, Marseille, France. ·Oncotarget · Pubmed #25481873.

ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) is a disease with a great heterogeneity in the response to treatments. To improve the responsiveness to treatments there are two different approaches, the first one consist to develop new and more efficient drugs that intent to cure all patients and the second one is to use already-approved drugs, alone or in combination, but selecting beforehand the most sensitive patients. In this work we explored the efficiency of the second possibility. We developed a collection of 17 PDAC samples collected by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery and preserved as xenografts and as primary cultures. This collection was characterized at molecular level by a transcriptomic analysis using an Affymetrix approach. In this paper we present data demonstrating that a subgroup of PDAC responds to low doses of 5-aza-dC. These tumors show a specific RNA expression profile that could serve as a marker, but there is no correlation with Dnmt1, Dnmt3A or Dnmt3B expression. Responder tumors corresponded to well-differentiated samples and longer survival patients. In conclusion, we present data obtained with the well-known drug 5-aza-dC as a proof of concept that a drug that seems to be inefficient in solid tumors in general could be applicable to a particular subgroup of patients with PDAC.

12 Article Further characterization of HDAC and SIRT gene expression patterns in pancreatic cancer and their relation to disease outcome. 2014

Ouaïssi, Mehdi / Silvy, Françoise / Loncle, Céline / Ferraz da Silva, Diva / Martins Abreu, Carla / Martinez, Emmanuelle / Berthézene, Patrick / Cadra, Sophie / Le Treut, Yves Patrice / Hardwigsen, Jean / Sastre, Bernard / Sielezneff, Igor / Benkoel, Liliane / Delgrande, Jean / Ouaissi, Ali / Iovanna, Juan / Lombardo, Dominique / Mas, Eric. ·Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France; AP-HM, Timone Hospital, Department of Digestive and visceral Surgery, Marseille, France. · Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France. · Aix-Marseille University, CRCM, UMR_S 1068, Institut Paoli-Calmettes, CNRS, UMR7258, Marseille, France; INSERM, UMR 1068, Marseille, France. · Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France; Faculdade de Farmácia da Universidade do Porto, Porto, Portugal. · AP-HM, La Conception Hospital, Department of hepatic transplantation and general surgery, Marseille, France; Aix-Marseille University, Marseille, France. · AP-HM, Timone Hospital, Department of Digestive and visceral Surgery, Marseille, France; Aix-Marseille University, Marseille, France. · INSERM UMR 911, Marseille, France. · AP-HM, Timone Hospital, Department of histopathology, Marseille, France. · Faculdade de Farmácia da Universidade do Porto, Porto, Portugal. ·PLoS One · Pubmed #25275504.

ABSTRACT: Ductal adenocarcinoma of the pancreas is ranking 4 for patient' death from malignant disease in Western countries, with no satisfactory treatment. We re-examined more precisely the histone deacetylases (HDAC) and Sirtuin (SIRT) gene expression patterns in pancreatic cancer with more pancreatic tumors and normal tissues. We also examined the possible relationship between HDAC gene expression levels and long term disease outcome. Moreover, we have evaluated by using an in vitro model system of human pancreatic tumor cell line whether HDAC7 knockdown may affect the cell behavior. We analyzed 29 pancreatic adenocarcinoma (PA), 9 chronic pancreatitis (CP), 8 benign pancreatic (BP) and 11 normal pancreatic tissues. Concerning pancreatic adenocarcinoma, we were able to collect biopsies at the tumor periphery. To assess the possible involvement of HDAC7 in cell proliferation capacity, we have generated recombinant human Panc-1 tumor which underexpressed or overexpressed HDAC7. The expression of HDAC1,2,3,4,7 and Nur77 increased in PA samples at levels significantly higher than those observed in the CP group (p = 0.0160; 0.0114; 0.0227; 0.0440; 0.0136; 0.0004, respectively). The expression of HDAC7, was significantly greater in the PA compared with BP tissue samples (p = 0.05). Mean mRNA transcription levels of PA for HDAC7 and HDAC2 were higher when compared to their counterpart biopsies taken at the tumor periphery (p = 0.0346, 0.0053, respectively). Moreover, the data obtained using confocal microscopy and a quantitative method of immunofluorescence staining strongly support the HDAC7 overexpression in PA surgical specimens. The number of deaths and recurrences at the end of follow up were significantly greater in patients with overexpression of HDAC7. Interestingly, the rate of growth was significantly reduced in the case of cell carrying shRNA construct targeting HDAC7 encoding gene when compared to the parental Panc-1 tumor cells (p = 0.0015) at 48 h and 96 h (p = 0.0021). This study strongly support the notion that HDAC7play a role in pancreatic adenocarcinoma progression.

13 Article IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation. 2014

Garcia, Maria Noé / Grasso, Daniel / Lopez-Millan, Maria Belen / Hamidi, Tewfik / Loncle, Celine / Tomasini, Richard / Lomberk, Gwen / Porteu, Françoise / Urrutia, Raul / Iovanna, Juan L. · ·J Clin Invest · Pubmed #25250570.

ABSTRACT: Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.

14 Article Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis. 2014

Cano, Carla E / Hamidi, Tewfik / Garcia, Maria Noé / Grasso, Daniel / Loncle, Céline / Garcia, Stéphane / Calvo, Ezequiel / Lomberk, Gwen / Dusetti, Nelson / Bartholin, Laurent / Urrutia, Raul / Iovanna, Juan L. ·Centre de Recherche en Carcérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille University and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, , Marseille, France. ·Gut · Pubmed #24026351.

ABSTRACT: BACKGROUND: Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for Kras(G12D)-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer. METHODS: We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-Kras(G12D);Ink4a/Arf(fl/fl)(KIC) mice. RESULTS: Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1(wt);KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1(wt);KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1(wt);KIC cells. Moreover, Nupr1-deficient and Nurpr1(wt);KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness. CONCLUSIONS: According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.

15 Article Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. 2013

Guillaumond, Fabienne / Leca, Julie / Olivares, Orianne / Lavaut, Marie-Noëlle / Vidal, Nicolas / Berthezène, Patrice / Dusetti, Nelson Javier / Loncle, Céline / Calvo, Ezequiel / Turrini, Olivier / Iovanna, Juan Lucio / Tomasini, Richard / Vasseur, Sophie. ·Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, F-13009 Marseille, France. ·Proc Natl Acad Sci U S A · Pubmed #23407165.

ABSTRACT: Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the "glycolytic" switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.

16 Article Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer. 2012

Cano, Carla E / Sandí, María José / Hamidi, Tewfik / Calvo, Ezequiel L / Turrini, Olivier / Bartholin, Laurent / Loncle, Céline / Secq, Véronique / Garcia, Stéphane / Lomberk, Gwen / Kroemer, Guido / Urrutia, Raul / Iovanna, Juan L. ·INSERM U, CRCM, Cell Stress, Marseille, France. ·EMBO Mol Med · Pubmed #22821859.

ABSTRACT: Pancreatic adenocarcinoma (PDAC) is an extremely deadly disease for which all treatments available have failed to improve life expectancy significantly. This may be explained by the high metastatic potential of PDAC cells, which results from their dedifferentiation towards a mesenchymal phenotype. Some PDAC present cell-in-cell structures whose origin and significance are currently unknown. We show here that cell-in-cells form after homotypic cell cannibalism (HoCC). We found PDAC patients whose tumours display HoCC develop less metastasis than those without. In vitro, HoCC was promoted by inactivation of the nuclear protein 1 (Nupr1), and was enhanced by treatment with transforming growth factor β. HoCC ends with death of PDAC cells, consistent with a metastasis suppressor role for this phenomenon. Hence, our data indicates a protective role for HoCC in PDAC and identifies Nupr1 as a molecular regulator of this process.

17 Article p8 expression controls pancreatic cancer cell migration, invasion, adhesion, and tumorigenesis. 2011

Sandi, Maria Jose / Hamidi, Tewfik / Malicet, Cédric / Cano, Carla / Loncle, Céline / Pierres, Anne / Dagorn, Jean Charles / Iovanna, Juan L. ·INSERM U624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille, France. ·J Cell Physiol · Pubmed #21344397.

ABSTRACT: p8 is a stress gene whose activity is necessary for tumor development and progression. The acquisition of invasive properties by transformed cells is a key event in tumor development. In order to establish whether p8 is involved or not in this phenomenon, we assessed the capacity of p8 at influencing cell adhesion, migration, invasion, and tumorigenesis of pancreatic cancer cells. p8 expression was knocked down by a small interfering RNA (siRNA) in pancreatic cancer-derived Panc-1 and MiaPaCa-2 cells and subsequent changes in cell adhesion, migration, invasion, and tumorigenesis were assessed. Influence of p8 silencing on gene expression was analyzed using cDNA microarrays. The influence of inhibiting CDC42, one of the genes most over-expressed in p8-silenced cells, on the changes observed in p8-silenced cells was also evaluated. Finally, the tumorigenic capacities of Panc-1 cells transfected with control siRNA or p8 siRNA were compared by assessing their ability to form colonies in soft agar and to grow as xenografts in nude mice. Knocking-down p8 in pancreatic cancer cells in vitro decreased migration and invasion while increasing cell adhesion; over-expression produced the opposite effect. Knocking down CDC42 reversed almost completely the effects of silencing p8 in vitro. Finally, cells transfected with p8 siRNA were almost unable to form colonies in soft agar. In addition, p8-deficient Panc-1 cells did not develop tumors when injected subcutaneously in nude mice. In conclusion, p8 expression controls pancreatic cancer cell migration, invasion and adhesion, three processes required for metastasis, at least in part, through CDC42, a major regulator of cytoskeleton organization.