Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Nelson Javier Dusetti
Based on 23 articles published since 2009
(Why 23 articles?)
||||

Between 2009 and 2019, N. Dusetti wrote the following 23 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Speeding towards individualized treatment for pancreatic cancer by taking an alternative road. 2017

Iovanna, Juan / Dusetti, Nelson. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université, Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. Electronic address: juan.iovanna@inserm.fr. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université, Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. ·Cancer Lett · Pubmed #28947138.

ABSTRACT: Accumulation of genetic mutations drives the development of pancreatic ductal adenocarcinoma (PDAC). Contrary to what it is expected, however, genetic analyses, no matter how precise or detailed, do not allow the identification of patient groups with different clinical outcomes or the selection of specific treatments. In fact, clinical outcome and sensitivity to treatments are associated with a given phenotype and are therefore associated at a transcriptomic level. In practical terms, therefore, the most appropriate readout for phenotypically stratifying PDACs should be transcriptomic and not genetic analysis. Recently data indicate that studying the expression of a selected gene set could inform selection of the most appropriate treatment for patients, moving towards an individualized medicine approach for this dismal disease. We are optimizing this approach by developing a platform based on obtaining organoids directly from surgical as well as endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsies of tumors, which serve as a source of RNA, allowing determination of the transcription level of some informative genes. We are convinced that in the near future, the treatment of cancers will be preceded by an extensive molecular characterization of cancer cells in order to select the most appropriate treatments.

2 Review Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. 2013

McCleary-Wheeler, Angela L / Lomberk, Gwen A / Weiss, Frank U / Schneider, Günter / Fabbri, Muller / Poshusta, Tara L / Dusetti, Nelson J / Baumgart, Sandra / Iovanna, Juan L / Ellenrieder, Volker / Urrutia, Raul / Fernandez-Zapico, Martin E. ·Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Rochester, MN, USA. ·Cancer Lett · Pubmed #23073473.

ABSTRACT: During the last couple decades, we have significantly advanced our understanding of mechanisms underlying the development of pancreatic ductual adenocarcinoma (PDAC). In the late 1990s into the early 2000s, a model of PDAC development and progression was developed as a multi-step process associated with the accumulation of somatic mutations. The correlation and association of these particular genetic aberrations with the establishment and progression of PDAC has revolutionized our understanding of this process. However, this model leaves out other molecular events involved in PDAC pathogenesis that contribute to its development and maintenance, specifically those being epigenetic events. Thus, a new model considering the new scientific paradigms of epigenetics will provide a more comprehensive and useful framework for understanding the pathophysiological mechanisms underlying this disease. Epigenetics is defined as the type of inheritance not based on a particular DNA sequence but rather traits that are passed to the next generation via DNA and histone modifications as well as microRNA-dependent mechanisms. Key tumor suppressors that are well established to play a role in PDAC may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. A noteworthy characteristic of epigenetic-based inheritance is its reversibility, which is in contrast to the stable nature of DNA sequence-based alterations. Given this nature of epigenetic alterations, it becomes imperative that our understanding of epigenetic-based events promoting and maintaining PDAC continues to grow.

3 Article [Multi-omic approaches reveal new therapeutic targets for the treatment of pancreatic cancer]. 2018

Nicolle, Rémy / Blum, Yuna / Marisa, Laetitia / Dusetti, Nelson / Iovanna, Juan. ·Programme cartes d'identité des tumeurs (CIT), Ligue nationale contre le cancer, 14, rue Corvisart, 75013 Paris, France. · Centre de recherche en cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix Marseille université, 163, avenue de Luminy, 13288 Marseille, France. ·Med Sci (Paris) · Pubmed #29900832.

ABSTRACT: -- No abstract --

4 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.

5 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.

6 Article Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas. 2018

Lupinacci, Renato M / Goloudina, Anastasia / Buhard, Olivier / Bachet, Jean-Baptiste / Maréchal, Raphaël / Demetter, Pieter / Cros, Jérôme / Bardier-Dupas, Armelle / Collura, Ada / Cervera, Pascale / Scriva, Aurélie / Dumont, Sylvie / Hammel, Pascal / Sauvanet, Alain / Louvet, Christophe / Delpéro, Jean-Robert / Paye, François / Vaillant, Jean-Christophe / André, Thierry / Closset, Jean / Emile, Jean-François / Van Laethem, Jean-Luc / Jonchère, Vincent / Abd Alsamad, Issam / Antoine, Martine / Rodenas, Anita / Fléjou, Jean-François / Dusetti, Nelson / Iovanna, Juan / Duval, Alex / Svrcek, Magali. ·INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; Groupe Hospitalier Diaconesses - Croix Saint-Simon, Service de Chirurgie Digestive, Viscérale et Endocrinienne, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Inovarion F - 75013, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service d'Hépato-Gastro-Entérologie, Paris, France. · Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. · Department of Pathology, Erasme Hospital, Brussels, Belgium. · AP-HP, Service d'Anatomie et Cytologie Pathologiques, Hôpital Beaujon, Clichy, France; Université Paris Diderot - Paris 7, Paris, France. · AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service d'Anatomie et Cytologie Pathologiques, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. · AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France. · Université Paris Diderot - Paris 7, Paris, France; AP-HP, Hôpital Beaujon, Department of Gastroenterology, Pôle des Maladies de l'Appareil Digestif (PMAD), Clichy, France. · Université Paris Diderot - Paris 7, Paris, France; AP-HP, Hôpital Beaujon, Department of Hepato-Pancreato-Biliary Surgery, Pôle des Maladies de l'Appareil Digestif (PMAD), Clichy, France. · Department of Oncology, Institut Mutualiste Montsouris, Paris, France. · Department of Digestive Surgical Oncology, Paoli Calmettes Institute, Comprehensive Cancer Centre, Marseille, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service de Chirurgie Générale et Digestive, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Chirurgie Digestive et Hépato-bilio-pancréatique, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; Department of Oncology, Hôpital Saint Antoine, Paris, France. · EA4340 and Service d'Anatomie et Cytologie Pathologiques, Hôpital Ambroise Paré, AP-HP and Versailles University, Boulogne, France. · Hôpital Intercommunal de Créteil, Service d'Anatomie et Cytologie Pathologiques, Créteil, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Tenon, Service d'Anatomie et Cytologie Pathologiques, Paris, 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. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France. Electronic address: alex.duval@inserm.fr. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. Electronic address: magali.svrcek@aphp.fr. ·Gastroenterology · Pubmed #29158190.

ABSTRACT: Microsatellite instability (MSI) caused by mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical analyses of a 445 PDAC specimens, collected from consecutive patients at multiple centers, to identify those with dMMR, based on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2. We detected dMMR in 1.6% of tumor samples; we found dMMR in a larger proportion of intraductal papillary mucinous neoplasms-related tumors (4/58, 6.9%) than non- intraductal papillary mucinous neoplasms PDAC (5/385, 1.3%) (P = .02). PDACs with dMMR contained potentially immunogenic mutations because of MSI in coding repeat sequences. PDACs with dMMR or MSI had a higher density of CD8+ T cells at the invasive front than PDACs without dMMR or MSI (P = .08; Fisher exact test). A higher proportion of PDACs with dMMR or MSI expressed the CD274 molecule (PD-L1, 8/9) than PDACs without dMMR or MSI (4/10) (P = .05). Times of disease-free survival and overall survival did not differ significantly between patients with PDACs with dMMR or MSI vs without dMMR or MSI. Studies are needed to determine whether these features of PDACs with dMMR or MSI might serve as prognostic factors.

7 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.

8 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:

9 Article GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. 2017

Martinelli, Paola / Carrillo-de Santa Pau, Enrique / Cox, Trevor / Sainz, Bruno / Dusetti, Nelson / Greenhalf, William / Rinaldi, Lorenzo / Costello, Eithne / Ghaneh, Paula / Malats, Núria / Büchler, Markus / Pajic, Marina / Biankin, Andrew V / Iovanna, Juan / Neoptolemos, John / Real, Francisco X. ·Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain. · Cancer Progression and Metastasis Group, Institute for Cancer Research, Medical University Wien, Vienna, Austria. · Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK. · NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain. · 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. · Institute for Research in Biomedicine (IRB), Barcelona, Spain. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain. · Department for General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. ·Gut · Pubmed #27325420.

ABSTRACT: BACKGROUND AND AIMS: The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. DESIGN: We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. RESULTS: GATA6 inhibits the epithelial-mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET CONCLUSIONS: We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.

10 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.

11 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.

12 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.

13 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.

14 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.

15 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.

16 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.

17 Article The E3 ubiquitin ligase thyroid hormone receptor-interacting protein 12 targets pancreas transcription factor 1a for proteasomal degradation. 2014

Hanoun, Naïma / Fritsch, Samuel / Gayet, Odile / Gigoux, Véronique / Cordelier, Pierre / Dusetti, Nelson / Torrisani, Jérôme / Dufresne, Marlène. ·From the INSERM UMR1037, Cancer Research Center of Toulouse (CRCT), University of Toulouse III Paul Sabatier, 31037 Toulouse, France. · the Cancer Research Center of Marseille, INSERM UMR1068, Paoli-Calmettes Institute, University of Aix-Marseille, CNRS UMR7258, 13273 Marseille, France. · EA 4552, University of Toulouse III Paul Sabatier, 31432 Toulouse, France, and. · From the INSERM UMR1037, Cancer Research Center of Toulouse (CRCT), University of Toulouse III Paul Sabatier, 31037 Toulouse, France, marlene.dufresne@inserm.fr. ·J Biol Chem · Pubmed #25355311.

ABSTRACT: Pancreas transcription factor 1a (PTF1a) plays a crucial role in the early development of the pancreas and in the maintenance of the acinar cell phenotype. Several transcriptional mechanisms regulating expression of PTF1a have been identified. However, regulation of PTF1a protein stability and degradation is still unexplored. Here, we report that inhibition of proteasome leads to elevated levels of PTF1a and to the existence of polyubiquitinated forms of PTF1a. We used the Sos recruitment system, an alternative two-hybrid system method to detect protein-protein interactions in the cytoplasm and to map the interactome of PTF1a. We identified TRIP12 (thyroid hormone receptor-interacting protein 12), an E3 ubiquitin-protein ligase as a new partner of PTF1a. We confirmed PTF1a/TRIP12 interaction in acinar cell lines and in co-transfected HEK-293T cells. The protein stability of PTF1a is significantly increased upon decreased expression of TRIP12. It is reduced upon overexpression of TRIP12 but not a catalytically inactive TRIP12-C1959A mutant. We identified a region of TRIP12 required for interaction and identified lysine 312 of PTF1a as essential for proteasomal degradation. We also demonstrate that TRIP12 down-regulates PTF1a transcriptional and antiproliferative activities. Our data suggest that an increase in TRIP12 expression can play a part in PTF1a down-regulation and indicate that PTF1a/TRIP12 functional interaction may regulate pancreatic epithelial cell homeostasis.

18 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.

19 Article Oxidative stress induced by inactivation of TP53INP1 cooperates with KrasG12D to initiate and promote pancreatic carcinogenesis in the murine pancreas. 2013

Al Saati, Talal / Clerc, Pascal / Hanoun, Naïma / Peuget, Sylvain / Lulka, Hubert / Gigoux, Véronique / Capilla, Florence / Béluchon, Benoît / Couvelard, Anne / Selves, Janick / Buscail, Louis / Carrier, Alice / Dusetti, Nelson / Dufresne, Marlène. ·Histology Facility, INSERM-US006 ANEXPLO/CREFRE, Toulouse, France. ·Am J Pathol · Pubmed #23578383.

ABSTRACT: Tumor protein p53-induced nuclear protein 1 (TP53INP1) is involved in cell stress response. Its expression is lost at the pancreatic intraepithelial neoplasia 1b (PanIN1b)/PanIN2 stage of pancreatic carcinogenesis. Our objective was to determine whether TP53INP1 loss of expression contributes to pancreatic cancer formation in a conditional KrasG12D mouse model. We generated Kras-INP1KO mice using LSL-Kras(G12D/+);Pdx1-Cre(+/-) mice (Kras mice) and TP53INP1(-/-) mice. Analysis of pancreases during ageing shows that in the presence of activated Kras, TP53INP1 loss of expression accelerated PanIN formation and increased pancreatic injury and the number of high-grade lesions as compared with what occurs in Kras mice. Moreover, cystic lesions resembling intraductal papillary mucinous neoplasm (IPMN) were observed as early as 2 months of age. Remarkably, TP53INP1 is down-regulated in human IPMN. Activation of the small GTPase Rac1 shows that more oxidative stress is generated in Kras-INP1KO than in Kras mice pancreas despite elevated levels of the Nrf2 antioxidant regulator. We firmly establish the link between Kras-INP1KO pancreatic phenotype and oxidative stress with rescue of the phenotype by the antioxidant action of N-acetylcysteine. Our data provide in vivo functional demonstration that TP53INP1 deficiency accelerates progression of pancreatic cancer, underlining its role in the occurrence of IPMN and highlighting the importance of TP53INP1 in the control of oxidative status during development of pancreatic cancer.

20 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.

21 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.

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.

23 Article CIP4 is a new ArgBP2 interacting protein that modulates the ArgBP2 mediated control of WAVE1 phosphorylation and cancer cell migration. 2010

Roignot, J / Taïeb, D / Suliman, M / Dusetti, N J / Iovanna, J L / Soubeyran, P. ·INSERM, U.624, Parc Scientifique de Luminy, Marseille, France. ·Cancer Lett · Pubmed #19631450.

ABSTRACT: ArgBP2 is a multi-adapter protein involved in signal transduction associated to the cytoskeleton and was shown to regulate the migration and adhesion of pancreatic cancer cells thereby modulating their tumorigenicity. Here we describe the interaction of ArgBP2 with CIP4, a new associated protein identified by yeast two-hybrid. We found that both proteins modulated their reciprocal tyrosine phosphorylation catalyzed by the non-receptor tyrosine kinase c-Abl. We observed that, like ArgBP2, CIP4 directly interacted with WAVE1 and could enhance its phosphorylation by c-Abl. ArgBP2 and CIP4 acted synergistically to increase WAVE1 tyrosine phosphorylation. Finally, we could show that CIP4 was dispensable for the ArgBP2 induced blockade of cell migration whereas its overexpression was deleterious for this important function of ArgBP2.