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Pancreatic Neoplasms: HELP
Articles by Stephane Garcia
Based on 22 articles published since 2010
(Why 22 articles?)
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Between 2010 and 2020, S. Garcia wrote the following 22 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial A prospective clinical and biological database for pancreatic adenocarcinoma: the BACAP cohort. 2018

Canivet, Cindy / Gourgou-Bourgade, Sophie / Napoléon, Bertrand / Palazzo, Laurent / Flori, Nicolas / Guibert, Pierre / Piessen, Guillaume / Farges-Bancel, Dominique / Seitz, Jean-François / Assenat, Eric / Vendrely, Véronique / Truant, Stéphanie / Vanbiervliet, Geoffroy / Berthelémy, Philippe / Garcia, Stéphane / Gomez-Brouchet, Anne / Buscail, Louis / Bournet, Barbara / Anonymous4030965. ·The Department of Gastroenterology and Pancreatology, CHU - Rangueil and the University of Toulouse, 1 avenue Jean Poulhès, TSA 50032, 31059, Toulouse Cedex 9, France. · The Biometrics Unit - CTD Inca, the Cancer Institute and the University of Montpellier, Montpellier, France. · The Department of Gastroenterology, Jean Mermoz Hospital, Ramsay Générale de Santé, Lyon, France. · The Department of Endoscopy, Trocadéro Clinic, Paris, France. · The Department of Oncology, the Cancer Institute and the University of Montpellier, Montpellier, France. · The Department of Oncology, Leon Bérard Institute, Lyon, France. · Univ. Lille, Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, F-59000, Lille, France. · The Department of Internal Medicine, Saint-Louis Hospital and Paris 7 Diderot University, Paris, France. · The Department of Oncology, CHU - La Timone and the University of Marseille, Marseille, France. · The Department of Oncology, CHU - ST-Eloi and the University of Montpellier, Montpellier, France. · The Department of Oncology and Radiotherapy, CHU - Haut-Levêque and the University of Bordeaux, Bordeaux, France. · The Department of Digestive Surgery and Transplantation, the CHU and the University of Lille, Lille, France. · The Department of Gastroenterology, CHU - L'Archet and the University of Nice, Nice, France. · The Department of Gastroenterology, Pau Hospital, Pau, France. · The Department of Pathology, CHU - Nord and the University of Marseille, Marseille, France. · The Biobank, the Cancer Institute and the University of Toulouse, Toulouse, France. · The Department of Gastroenterology and Pancreatology, CHU - Rangueil and the University of Toulouse, 1 avenue Jean Poulhès, TSA 50032, 31059, Toulouse Cedex 9, France. Bournet.b@chu-toulouse.fr. ·BMC Cancer · Pubmed #30326968.

ABSTRACT: BACKGROUND: The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically. METHODS: Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at - 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy. DISCUSSION: The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02818829 . Registration date: June 30, 2016.

2 Article Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. 2018

Lomberk, Gwen / Blum, Yuna / Nicolle, Rémy / Nair, Asha / Gaonkar, Krutika Satish / Marisa, Laetitia / Mathison, Angela / Sun, Zhifu / Yan, Huihuang / Elarouci, Nabila / Armenoult, Lucile / Ayadi, Mira / Ordog, Tamas / Lee, Jeong-Heon / Oliver, Gavin / Klee, Eric / Moutardier, Vincent / Gayet, Odile / Bian, Benjamin / Duconseil, Pauline / Gilabert, Marine / Bigonnet, Martin / Garcia, Stephane / Turrini, Olivier / Delpero, Jean-Robert / Giovannini, Marc / Grandval, Philippe / Gasmi, Mohamed / Secq, Veronique / De Reyniès, Aurélien / Dusetti, Nelson / Iovanna, Juan / Urrutia, Raul. ·Division of Research, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA. glomberk@mcw.edu. · Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 14 rue Corvisart, Paris, 75013, France. · Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA. · Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA. · Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA. · Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. · 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, 163 Avenue de Luminy, Marseille, 13288, France. · Hôpital Nord, Chemin des Bourrely, Marseille, 13015, France. · Institut Paoli-Calmettes, 232 Boulevard Sainte Marguerite, Marseille, 13009, France. · Hôpital de la Timone, 264 rue Saint-Pierre, Marseille, 13385, France. · 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, 163 Avenue de Luminy, Marseille, 13288, France. juan.iovanna@inserm.fr. · Division of Research, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA. rurrutia@mcw.edu. · Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA. rurrutia@mcw.edu. · Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA. rurrutia@mcw.edu. ·Nat Commun · Pubmed #29773832.

ABSTRACT: Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.

3 Article Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma. 2018

Siret, Carole / Dobric, Aurélie / Martirosyan, Anna / Terciolo, Chloé / Germain, Sébastien / Bonier, Renaté / Dirami, Thassadite / Dusetti, Nelson / Tomasini, Richard / Rubis, Marion / Garcia, Stéphane / Iovanna, Juan / Lombardo, Dominique / Rigot, Véronique / André, Frédéric. ·Aix-Marseille Université, Inserm UMR 911, CRO2, 27 blvd Jean Moulin, Marseille 13385, France. · 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 13009, France. · Hôpital Nord, Marseille 13015, France. ·Br J Cancer · Pubmed #29161242.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an extensive tissue invasion and an early formation of metastasis. Alterations in the expression of cadherins have been reported in PDAC. Yet, how these changes contribute to tumour progression is poorly understood. Here, we investigated the relationship between cadherins expression and PDAC development. METHODS: Cadherins expression was assessed by immunostaining in both human and murine tissue specimens. We have generated pancreatic cancer cell lines expressing both cadherin-1 and cadherin-3 or only one of these cadherins. Functional implications of such genetic alterations were analysed both in vitro and in vivo. RESULTS: Cadherin-3 is detected early at the plasma membrane during progression of pancreatic intraepithelial neoplasia 1 (PanIN-1) to PDAC. Despite tumoural cells turn on cadherin-3, a significant amount of cadherin-1 remains expressed at the cell surface during tumourigenesis. We found that cadherin-3 regulates tumour growth, while cadherin-1 drives type I collagen organisation in the tumour. In vitro assays showed that cadherins differentially participate to PDAC aggressiveness. Cadherin-3 regulates cell migration, whereas cadherin-1 takes part in the invadopodia activity. CONCLUSIONS: Our results show differential, but complementary, roles for cadherins during PDAC carcinogenesis and illustrate how their expression conditions the PDAC aggressiveness.

4 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.

5 Article Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. 2017

Olivares, Orianne / Mayers, Jared R / Gouirand, Victoire / Torrence, Margaret E / Gicquel, Tristan / Borge, Laurence / Lac, Sophie / Roques, Julie / Lavaut, Marie-Noëlle / Berthezène, Patrice / Rubis, Marion / Secq, Veronique / Garcia, Stéphane / Moutardier, Vincent / Lombardo, Dominique / Iovanna, Juan Lucio / Tomasini, Richard / Guillaumond, Fabienne / Vander Heiden, Matthew G / Vasseur, Sophie. ·Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, Marseille F-13009, France. · Institut Paoli-Calmettes (IPC), Marseille F-13009, France. · Unité Mixte de Recherche (UMR 7258), Centre National de la Recherche Scientifique (CNRS), Marseille F-13009, France. · Université Aix-Marseille, Marseille F-13284, France. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK. · Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. · Aix Marseille Univ, INSERM, CRO2, Marseille F-13005, France. · Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ·Nat Commun · Pubmed #28685754.

ABSTRACT: Tissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited. We show PDAC cells are able to take up collagen fragments, which can promote PDAC cell survival under nutrient limited conditions, and that collagen-derived proline contributes to PDAC cell metabolism. Finally, we show that proline oxidase (PRODH1) is required for PDAC cell proliferation in vitro and in vivo. Collectively, our results indicate that PDAC extracellular matrix represents a nutrient reservoir for tumour cells highlighting the metabolic flexibility of this cancer.

6 Article Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs? 2017

Mohamed, Amira / Romano, David / Saveanu, Alexandru / Roche, Catherine / Albertelli, Manuela / Barbieri, Federica / Brue, Thierry / Niccoli, Patricia / Delpero, Jean-Robert / Garcia, Stephane / Ferone, Diego / Florio, Tullio / Moutardier, Vincent / Poizat, Flora / Barlier, Anne / Gerard, Corinne. ·Aix Marseille Univ, CNRS, CRN2M, Marseille, France. · APHM, Conception Hospital, Molecular Biology Laboratory, Marseille, France. · Department of Internal Medicine and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy. · APHM, Conception Hospital, Endocrinology Department, Marseille, France. · Paoli Calmettes Cancer Institute, Oncology Department, IPC CoE-ENETS, Marseille, France. · Paoli Calmettes Cancer Institute, Surgery Department, IPC CoE-ENETS, Marseille, France. · APHM, North Hospital, Pathology Laboratory, Marseille, France. · APHM, North Hospital, Surgery Department, Marseille, France. · Paoli Calmettes Cancer Institute, Biopathology Department, IPC CoE-ENETS, Marseille, France. ·Oncotarget · Pubmed #28454119.

ABSTRACT: Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

7 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:

8 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.

9 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.

10 Article A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination. 2015

Collignon, Aurélie / Perles-Barbacaru, Adriana Teodora / Robert, Stéphane / Silvy, Françoise / Martinez, Emmanuelle / Crenon, Isabelle / Germain, Sébastien / Garcia, Stéphane / Viola, Angèle / Lombardo, Dominique / Mas, Eric / Béraud, Evelyne. ·Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France. · Inserm, UMR_S 911, Marseille, France. · Aix-Marseille Université, CNRS, CRMBM, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, Marseille, France. · Aix-Marseille Université, VRCM, Vascular Research Center of Marseilles, Marseille, France. · Inserm, UMR_S_1076, Marseille, France. · APHM, Hôpital Nord, Laboratoire d'Anatomie-Pathologie, Marseille, France. · Aix-Marseille Université, Marseille, France. ·Oncotarget · Pubmed #26405163.

ABSTRACT: Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC.

11 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.

12 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.

13 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.

14 Article Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling. 2015

Secq, V / Leca, J / Bressy, C / Guillaumond, F / Skrobuk, P / Nigri, J / Lac, S / Lavaut, M-N / Bui, T-T / Thakur, A K / Callizot, N / Steinschneider, R / Berthezene, P / Dusetti, N / Ouaissi, M / Moutardier, V / Calvo, E / Bousquet, C / Garcia, S / Bidaut, G / Vasseur, S / Iovanna, J L / Tomasini, R. ·1] CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France [2] Department of Pathology, Hospital North/Mediterranean University, Marseille, France. · CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France. · Neuronexperts, Medical North Faculty, Marseille, France. · Aix-Marseille University, INSERM, CRO2, UMR 911, Marseille 13385, France. · Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec City, QCue, Canada. · INSERM UMR 1037, CRCT, University Toulouse III, Toulouse, France. ·Cell Death Dis · Pubmed #25590802.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/β-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.

15 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.

16 Article Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. 2014

Mohamed, Amira / Blanchard, Marie-Pierre / Albertelli, Manuela / Barbieri, Federica / Brue, Thierry / Niccoli, Patricia / Delpero, Jean-Robert / Monges, Genevieve / Garcia, Stephane / Ferone, Diego / Florio, Tullio / Enjalbert, Alain / Moutardier, Vincent / Schonbrunn, Agnes / Gerard, Corinne / Barlier, Anne / Saveanu, Alexandru. ·Aix-Marseille UniversitéCNRS, CRN2M-UMR 7286, Faculté de Médecine, Secteur Nord - CS80011, 51, Bd Pierre Dramard, 13344 Marseille Cedex 15, FranceMolecular Biology LaboratoryAP-HM, Conception Hospital, 13385 Marseille, FranceAix-Marseille UniversitéCNRS, Plate-Forme de Recherche en Neurosciences PFRN, 13344 Marseille Cedex 15, FranceDepartment of Internal Medicine and Center of Excellence for Biomedical ResearchUniversity of Genova, Genova, ItalyEndocrinology DepartmentAP-HM, Timone Hospital, 13385 Marseille, FranceOncology DepartmentSurgery DepartmentBiopathology DepartmentPaoli Calmettes Cancer Institute, 13009 Marseille, FrancePathology LaboratorySurgery DepartmentAP-HM, Nord Hospital, 13015 Marseille, FranceDepartment of Integrative Biology and PharmacologyUniversity of Texas, Texas 77225, Houston, USAAix-Marseille UniversitéCNRS, CRN2M-UMR 7286, Faculté de Médecine, Secteur Nord - CS80011, 51, Bd Pierre Dramard, 13344 Marseille Cedex 15, FranceMolecular Biology LaboratoryAP-HM, Conception Hospital, 13385 Marseille, FranceAix-Marseille UniversitéCNRS, Plate-Forme de Recherche en Neurosciences PFRN, 13344 Marseille Cedex 15, FranceDepartment of Internal Medicine and Center of Excellence for Biomedical ResearchUniversity of Genova, Genova, ItalyEndocrinology DepartmentAP-HM, Timone Hospital, 13385 Marseille, FranceOncology DepartmentSurgery DepartmentBiopathology DepartmentPaoli Calmettes Cancer Institute, 13009 Marseille, FrancePathology LaboratorySurgery DepartmentAP-HM, Nord Hospital, 13015 Marseille, FranceDepartment of Integrative Biology and PharmacologyUniversity of Texas, Texas 77225, Houston, USA. · Aix-Marseille UniversitéCNRS, CRN2M-UMR 7286, Faculté de Médecine, Secteur Nord - CS80011, 51, Bd Pierre Dramard, 13344 Marseille Cedex 15, FranceMolecular Biology LaboratoryAP-HM, Conception Hospital, 13385 Marseille, FranceAix-Marseille UniversitéCNRS, Plate-Forme de Recherche en Neurosciences PFRN, 13344 Marseille Cedex 15, FranceDepartment of Internal Medicine and Center of Excellence for Biomedical ResearchUniversity of Genova, Genova, ItalyEndocrinology DepartmentAP-HM, Timone Hospital, 13385 Marseille, FranceOncology DepartmentSurgery DepartmentBiopathology DepartmentPaoli Calmettes Cancer Institute, 13009 Marseille, FrancePathology LaboratorySurgery DepartmentAP-HM, Nord Hospital, 13015 Marseille, FranceDepartment of Integrative Biology and PharmacologyUniversity of Texas, Texas 77225, Houston, USA. · Aix-Marseille UniversitéCNRS, CRN2M-UMR 7286, Faculté de Médecine, Secteur Nord - CS80011, 51, Bd Pierre Dramard, 13344 Marseille Cedex 15, FranceMolecular Biology LaboratoryAP-HM, Conception Hospital, 13385 Marseille, FranceAix-Marseille UniversitéCNRS, Plate-Forme de Recherche en Neurosciences PFRN, 13344 Marseille Cedex 15, FranceDepartment of Internal Medicine and Center of Excellence for Biomedical ResearchUniversity of Genova, Genova, ItalyEndocrinology DepartmentAP-HM, Timone Hospital, 13385 Marseille, FranceOncology DepartmentSurgery DepartmentBiopathology DepartmentPaoli Calmettes Cancer Institute, 13009 Marseille, FrancePathology LaboratorySurgery DepartmentAP-HM, Nord Hospital, 13015 Marseille, FranceDepartment of Integrative Biology and PharmacologyUniversity of Texas, Texas 77225, Houston, USAAix-Marseille UniversitéCNRS, CRN2M-UMR 7286, Faculté de Médecine, Secteur Nord - CS80011, 51, Bd Pierre Dramard, 13344 Marseille Cedex 15, FranceMolecular Biology LaboratoryAP-HM, Conception Hospital, 13385 Marseille, FranceAix-Marseille UniversitéCNRS, Plate-Forme de Recherche en Neurosciences PFRN, 13344 Marseille Cedex 15, FranceDepartment of Internal Medicine and Center of Excellence for Biomedical ResearchUniversity of Genova, Genova, ItalyEndocrinology DepartmentAP-HM, Timone Hospital, 13385 Marseille, FranceOncology DepartmentSurgery DepartmentBiopathology DepartmentPaoli Calmettes Cancer Institute, 13009 Marseille, FrancePathology LaboratorySurgery DepartmentAP-HM, Nord Hospital, 13015 Marseille, FranceDepartment of Integrative Biology and PharmacologyUniversity of Texas, Texas 77225, Houston, USA alexandru.saveanu@univ-amu.fr anne.barlier@univ-amu.fr. ·Endocr Relat Cancer · Pubmed #25012983.

ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.

17 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.

18 Article FGFR3 has tumor suppressor properties in cells with epithelial phenotype. 2013

Lafitte, Marie / Moranvillier, Isabelle / Garcia, Stéphane / Peuchant, Evelyne / Iovanna, Juan / Rousseau, Benoit / Dubus, Pierre / Guyonnet-Dupérat, Véronique / Belleannée, Geneviève / Ramos, Jeanne / Bedel, Aurélie / de Verneuil, Hubert / Moreau-Gaudry, François / Dabernat, Sandrine. ·INSERM U1035, Université Bordeaux Segalen, 146 rue Léo Saignat, Bordeaux 33076, France. ·Mol Cancer · Pubmed #23902722.

ABSTRACT: BACKGROUND: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical. RESULTS: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors. CONCLUSION: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

19 Article Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs. 2013

Gilabert, Marine / Vaccaro, Maria Inés / Fernandez-Zapico, Martin E / Calvo, Ezequiel L / Turrini, Olivier / Secq, Véronique / Garcia, Stéphane / Moutardier, Vincent / Lomberk, Gwen / Dusetti, Nelson / Urrutia, Raul / Iovanna, Juan L. ·Cancer Research Center of Marseille, INSERM U624, Marseille, France. ·J Cell Physiol · Pubmed #23460482.

ABSTRACT: We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.

20 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.

21 Article OGX-427 inhibits tumor progression and enhances gemcitabine chemotherapy in pancreatic cancer. 2011

Baylot, V / Andrieu, C / Katsogiannou, M / Taieb, D / Garcia, S / Giusiano, S / Acunzo, J / Iovanna, J / Gleave, M / Garrido, C / Rocchi, P. ·INSERM, U624 'Stress Cellulaire', Parc Scientifique et Technologique de Luminy, Marseille, France. ·Cell Death Dis · Pubmed #22012255.

ABSTRACT: Despite many advances in oncology, almost all patients with pancreatic cancer (PC) die of the disease. Molecularly targeted agents are offering hope for their potential role in helping translate the improved activity of combination chemotherapy into improved survival. Heat shock protein 27 (Hsp27) is a chaperone implicated in several pathological processes such as cancer. Further, Hsp27 expression becomes highly upregulated in cancer cells after chemotherapy. Recently, a modified antisense oligonucleotide that is complementary to Hsp27 (OGX-427) has been developed, which inhibits Hsp27 expression and enhances drug efficacy in cancer xenograft models. Phase II clinical trials using OGX-427 in different cancers like breast, ovarian, bladder, prostate and lung are in progress in the United States and Canada. In this study, we demonstrate using TMA of 181 patients that Hsp27 expression and phosphorylation levels increase in moderately differentiated tumors to become uniformly highly expressed in metastatic samples. Using MiaPaCa-2 cells grown both in vitro and xenografted in mice, we demonstrate that OGX-427 inhibits proliferation, induces apoptosis and also enhances gemcitabine chemosensitivity via a mechanism involving the eukaryotic translation initiation factor 4E. Collectively, these findings suggest that the combination of Hsp27 knockdown with OGX-427 and chemotherapeutic agents such as gemcitabine can be a novel strategy to inhibit the progression of pancreas cancer.

22 Article TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression. 2011

Seux, M / Peuget, S / Montero, M P / Siret, C / Rigot, V / Clerc, P / Gigoux, V / Pellegrino, E / Pouyet, L / N'Guessan, P / Garcia, S / Dufresne, M / Iovanna, J L / Carrier, A / André, F / Dusetti, N J. ·INSERM, U624 Stress cellulaire, Marseille, France. ·Oncogene · Pubmed #21339733.

ABSTRACT: Tumor protein 53 induced nuclear protein 1 (TP53INP1) is a p53 target gene that induces cell growth arrest and apoptosis by modulating p53 transcriptional activity. TP53INP1 interacts physically with p53 and is a major player in the p53-driven oxidative stress response. Previously, we demonstrated that TP53INP1 is downregulated in an early stage of pancreatic cancerogenesis and when restored is able to suppress pancreatic tumor development. TP53INP1 downregulation in pancreas is associated with an oncogenic microRNA miR-155. In the present work, we studied the effects of TP53INP1 on cell migration. We found that TP53INP1 inactivation correlates with increased cell migration both in vivo and in vitro. The impact of TP53INP1 expression on cell migration was studied in different cellular contexts: mouse embryonic fibroblast and different pancreatic cancer cell lines. Its expression decreases cell migration by the transcriptional downregulation of secreted protein acidic and rich in cysteine (SPARC). SPARC is a matrix cellular protein, which governs diverse cellular functions and has a pivotal role in regulating cell-matrix interactions, cellular proliferation and migration. SPARC was also showed to be upregulated in normal pancreas and in pancreatic intraepithelial neoplasia lesions in a pancreatic adenocarcinoma mouse model only in the TP53INP1-deficient animals. This novel TP53INP1 activity on the regulation of SPARC expression could explain in part its tumor suppressor function in pancreatic adenocarcinoma by modulating cellular spreading during the metastatic process.