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Pancreatic Neoplasms: HELP
Articles by Juan-Lucio Iovanna
Based on 79 articles published since 2009
(Why 79 articles?)
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Between 2009 and 2019, J. Iovanna wrote the following 79 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel. 2012

Van Laethem, J-L / Verslype, C / Iovanna, J L / Michl, P / Conroy, T / Louvet, C / Hammel, P / Mitry, E / Ducreux, M / Maraculla, T / Uhl, W / Van Tienhoven, G / Bachet, J B / Maréchal, R / Hendlisz, A / Bali, M / Demetter, P / Ulrich, F / Aust, D / Luttges, J / Peeters, M / Mauer, M / Roth, A / Neoptolemos, J P / Lutz, M / Anonymous6430701. ·Gastrointestinal Cancer Unit, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. jl.vanlaethem@erasme.ulb.ac.be ·Ann Oncol · Pubmed #21810728.

ABSTRACT: Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

2 Editorial IER3 in pancreatic carcinogenesis. 2015

Molejon, Maria Inés / Iovanna, Juan Lucio. ·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. ·Oncotarget · Pubmed #26158545.

ABSTRACT: -- No abstract --

3 Editorial Pancreatic cancer: molecular, biochemical, chemopreventive, and therapeutic aspects. 2010

Iovanna, Juan / Neira, José Luis. · ·ScientificWorldJournal · Pubmed #20890586.

ABSTRACT: -- No abstract --

4 Review Pancreatic Ductal Adenocarcinoma: A Strong Imbalance of Good and Bad Immunological Cops in the Tumor Microenvironment. 2018

Foucher, Etienne D / Ghigo, Clément / Chouaib, Salem / Galon, Jérôme / Iovanna, Juan / Olive, Daniel. ·Team Immunity and Cancer, CRCM, Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Marseille, France. · Team Cellular Stress, CRCM, Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Marseille, France. · INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par La Ligue Contre Le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. · Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates. · Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France. ·Front Immunol · Pubmed #29868007.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with very few available treatments. For many decades, gemcitabine was the only treatment for patients with PDAC. A recent attempt to improve patient survival by combining this chemotherapy with FOLFIRINOX and nab-paclitaxel failed and instead resulted in increased toxicity. Novel therapies are urgently required to improve PDAC patient survival. New treatments in other cancers such as melanoma, non-small-cell lung cancer, and renal cancer have emerged, based on immunotherapy targeting the immune checkpoints cytotoxic T-lymphocyte-associated antigen 4 or programmed death 1 ligand. However, the first clinical trials using such immune checkpoint inhibitors in PDAC have had limited success. Resistance to immunotherapy in PDAC remains unclear but could be due to tissue components (cancer-associated fibroblasts, desmoplasia, hypoxia) and to the imbalance between immunosuppressive and effector immune populations in the tumor microenvironment. In this review, we analyzed the presence of "good and bad immunological cops" in PDAC and discussed the significance of changes in their balance.

5 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.

6 Review [Autophagy contributes to the initiation of pancreatic cancer]. 2017

Iovanna, Juan L. ·Centre de recherche en cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR 7258, Aix-Marseille Université et Institut Paoli-Calmettes, Parc scientifique et technologique de Luminy, 163, avenue de Luminy, 13288 Marseille, France. ·Med Sci (Paris) · Pubmed #28367822.

ABSTRACT: The pancreatic adenocarcinoma initiation results from the interaction of genetic events combined with multiple other factors. Among the genetic alterations that contribute to the pathogenesis of this disease, the mutation of the KRAS oncogene is required but not sufficient to trigger this cancer. Pancreatitis, an inflammatory disease, facilitates and accelerates the transformation of pancreatic cells when the KRAS oncogene is mutated. Of note, the repertoire of molecular mediators of pancreatitis which are responsible of the promotion of KRAS-mediated transformation is not completely defined. Importantly, autophagy has been proposed as one of the cellular mechanisms contributing to pancreatic carcinogenesis, especially in the initial phases, in which the oncogene KRAS appears to play its leading role. In addition, autophagy is strongly induced during pancreatitis. Although some aspects of autophagy in pancreatic cancer development are not completely established, we can affirm that overexpression of VMP1, an inducer of autophagy which is specifically activated in pancreas during pancreatitis, improves the development of pancreatic precancerous lesions PanINs when the oncogene KRAS is mutated. In addition, inhibition of the autophagic flux with chloroquine inhibits the KRAS pro-tumor effect in the pancreas. In conclusion, activation of expression of VMP1 improves the pro-tumor role of KRAS in pancreas.

7 Review The promise of epigenomic therapeutics in pancreatic cancer. 2016

Lomberk, Gwen A / Iovanna, Juan / Urrutia, Raul. ·Laboratory of Epigenetics & Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry & Molecular Biology, Biophysics, & Medicine, Mayo Clinic, Rochester, MN, USA. · 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. ·Epigenomics · Pubmed #27337224.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is often viewed to arise primarily by genetic alterations. However, today we know that many aspects of the cancer phenotype require a crosstalk among these genetic alterations with epigenetic changes. Indeed, aberrant gene expression patterns, driven by epigenetics are fixed by altered signaling from mutated oncogenes and tumor suppressors to define the PDAC phenotype. This conceptual framework may have significant mechanistic value and could offer novel possibilities for treating patients affected with PDAC. In fact, extensive investigations are leading to the development of small molecule drugs that reversibly modify the epigenome. These new 'epigenetic therapeutics' discussed herein are promising to fuel a new era of studies, by providing the medical community with new tools to treat this dismal disease.

8 Review Pancreatic tumor cell metabolism: focus on glycolysis and its connected metabolic pathways. 2014

Guillaumond, Fabienne / Iovanna, Juan Lucio / Vasseur, Sophie. ·INSERM U1068, Centre de Recherche en Cancérologie de Marseille, France; Institut Paoli-Calmettes, France; CNRS, UMR7258, F-13009 Marseille, France; Université Aix-Marseille, F-13284 Marseille, France. ·Arch Biochem Biophys · Pubmed #24393743.

ABSTRACT: Because of lack of effective treatment, pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in Western countries, with a very weak improvement of survival rate over the last 40years. Defeat of numerous conventional therapies to cure this cancer makes urgent to develop new tools usable by clinicians for a better management of the disease. Aggressiveness of pancreatic cancer relies on its own hallmarks: a low vascular network as well as a prominent stromal compartment (desmoplasia), which creates a severe hypoxic environment impeding correct oxygen and nutrients diffusion to the tumoral cells. To survive and proliferate in those conditions, pancreatic cancer cells set up specific metabolic pathways to meet their tremendous energetic and biomass demands. However, as PDAC is a heterogenous tumor, a complex reprogramming of metabolic processes is engaged by cancer cells according to their level of oxygenation and nutrients supply. In this review, we focus on the glycolytic activity of PDAC and the glucose-connected metabolic pathways which contribute to the progression and dissemination of this disease. We also discuss possible therapeutic strategies targeting these pathways in order to cure this disease which still until now is resistant to numerous conventional treatments.

9 Review Mechanistic insights into self-reinforcing processes driving abnormal histogenesis during the development of pancreatic cancer. 2013

Iovanna, Juan L / Marks, David L / Fernandez-Zapico, Martin E / Urrutia, Raul. ·Cancer Research Center of Marseille, Inserm U1068, CNRS, UMR7258, Institute Paoli-Calmettes, Aix-Marseille University, Marseille, France. ·Am J Pathol · Pubmed #23375449.

ABSTRACT: Pancreatic ductal adenocarcinoma, one of the most feared lethal and painful diseases, is increasing in incidence. The poor prognosis of pancreatic ductal adenocarcinoma-affected patients primarily is owing to our inability to develop effective therapies. Mechanistic studies of genetic, epigenetic, and cell-to-cell signaling events are providing clues to molecular pathways that can be targeted in an attempt to cure this disease. The current review article seeks to draw inferences from available mechanistic knowledge to build a theoretical framework that can facilitate these approaches. This conceptual model considers pancreatic cancer as a tissue disease rather than an isolated epithelial cell problem, which develops and progresses in large part as a result of three positive feedback loops: i) genetic and epigenetic changes in epithelial cells modulate their interaction with mesenchymal cells to generate a dynamically changing process of abnormal histogenesis, which drives more changes; ii) the faulty tissue architecture of neoplastic lesions results in unsynchronized secretion of signaling molecules by cells, which generates an environment that is poor in oxygen and nutrients; and iii) the increased metabolic needs of rapidly dividing cells serve as an evolutionary pressure for them to adapt to this adverse microenvironment, leading to the emergence of resistant clones. We discuss how these concepts can guide mechanistic studies, as well as aid in the design of novel experimental therapeutics.

10 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.

11 Review Targeting heat shock response pathways to treat pancreatic cancer. 2012

Xia, Yi / Rocchi, Palma / Iovanna, Juan L / Peng, Ling. ·Centre Interdisciplinaire de Nanoscience de Marseille, Département de Chimie, CNRS UPR 3118, 163 Avenue de Luminy, 13288 Marseille, France. ·Drug Discov Today · Pubmed #21986108.

ABSTRACT: Pancreatic cancer belongs to the group of extremely aggressive human cancers; conventional cancer treatments have little impact. Increasing understanding of the pathways associated with pancreatic cancer progression has enabled the development of targeted therapy on this cancer. Heat shock proteins (HSPs) and related heat shock response (HSR) pathways control multiple important oncogenic pathways for pancreatic cancer development. Consequently, they represent promising novel targets for pancreatic cancer therapy. Various strategies have been proposed and elaborated to target HSPs/HSR in pancreatic cancer with the corresponding modulators, the details of which are highlighted in this review.

12 Review Stress proteins and pancreatic cancer metastasis. 2010

Cano, Carla E / Iovanna, Juan L. ·INSERM U.624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille, France. ·ScientificWorldJournal · Pubmed #20890585.

ABSTRACT: Tumor metastasis is challenged by its resistance to microenvironmental stress infringed during escape from the primary tumor and the colonization of a foreign secondary tissue. Because of its great metastatic potential and its strong resistance to anticancer drugs, pancreatic cancer is regarded as a paradigm of the adaptation of cancer cells to microenvironmental stress. Thus, to understand how pancreatic cancer cells adapt to the different endogenous and therapy-related stresses is crucial for understanding their etiology and for the development of new efficient anticancer strategies. This review summarizes the multiple functions accomplished by one major factor of pancreatic cancer cell stress response, the stress protein p8.

13 Review Epithelial-to-mesenchymal transition in pancreatic adenocarcinoma. 2010

Cano, Carla E / Motoo, Yoshiharu / Iovanna, Juan L. ·INSERM U624 Cell Stress, Biology of Pancreas Stress Laboratory, Marseille, France. carla.cano@inserm.fr ·ScientificWorldJournal · Pubmed #20890584.

ABSTRACT: Epithelial to mesenchymal transition (EMT) is a physiologic process that allows morphological and genetic changes of carcinoma cells from an epithelial to a mesenchymal phenotype, which is the basis of the high metastatic potential of pancreatic cancer cells. EMT is triggered by various tumor microenvironmental factors, including cytokines, growth factors, and chemotherapeutic agents. This review summarizes the state-of-the-art knowledge on the molecular mechanisms that support pancreatic cancer EMT and the evidences that support its involvement in invasiveness/ aggressiveness, and the drug resistance of pancreatic cancer cells.

14 Review A review of kinases implicated in pancreatic cancer. 2009

Giroux, Valentin / Dagorn, Jean-Charles / Iovanna, Juan L. ·INSERM U624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille Cedex 9, France. ·Pancreatology · Pubmed #20090395.

ABSTRACT: The current 5-year survival rate of pancreatic cancer is about 3% and the median survival less than 6 months because the chemotherapy and radiation therapy presently available provide only marginal benefit. Clearly, pancreatic cancer requires new therapeutic concepts. Recently, the kinase inhibitors imatinib and gefitinib, developed to treat chronic myelogenous leukaemia and breast cancer, respectively, gave very good results. Kinases are deregulated in many diseases, including cancer. Given that phosphorylation controls cell survival signalling, strategies targeting kinases should obviously improve cancer treatment. The purpose of this review is to summarize the present knowledge on kinases potentially usable as therapeutic targets in the treatment of pancreatic cancer. All clinical trials using available kinase inhibitors in monotherapy or in combination with chemotherapeutic drugs failed to improve survival of patients with pancreatic cancer. To detect kinases relevant to this disease, we undertook a systematic screening of the human kinome to define a 'survival kinase' catalogue for pancreatic cells. We selected 56 kinases that are potential therapeutic targets in pancreatic cancer. Preclinical studies using combined inhibition of PAK7, MAP3K7 and CK2 survival kinases in vitro and in vivo showed a cumulative effect on apoptosis induction. We also observed that these three kinases are rather specific of pancreatic cancer cells. In conclusion, if kinase inhibitors presently available are unfortunately not efficient for treating pancreatic cancer, recent data suggest that inhibitors of other kinases, involved more specifically in pancreatic cancer development, might, in the future, become interesting therapeutic targets.

15 Article Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis. 2018

Santofimia-Castaño, Patricia / Lan, Wenjun / Bintz, Jennifer / Gayet, Odile / Carrier, Alice / Lomberk, Gwen / Neira, José Luis / González, Antonio / Urrutia, Raul / Soubeyran, Philippe / 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. · Division of Research, Department of Surgery and the Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, USA. · Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Edificio Torregaitán, Avda. del Ferrocarril s/n, 03202, Elche, Alicante, Spain. · Cell Physiology Research Group, Department of Physiology, University of Extremadura, Caceres, 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. juan.iovanna@inserm.fr. ·Sci Rep · Pubmed #30451898.

ABSTRACT: It was already described that genetic inhibition of NUPR1 induces tumor growth arrest. In this paper we studied the metabolism changes after NUPR1 downregulation in pancreatic cancer cells, which results in a significant decrease of OXPHOS activity with a concomitant lower ATP production which precedes the necrotic cell death. We demonstrated that NUPR1 downregulation induces a mitochondrial failure with a loss of the mitochondrial membrane potential, a strong increase in ROS production and a concomitant relocalization of mitochondria to the vicinity of the endoplasmic reticulum (ER). In addition, the transcriptomic analysis of NUPR1-deficient cells shows a decrease in the expression of some ER stress response-associated genes. Indeed, in ER stressors-treated cells with thapsigargin, brefeldin A or tunicamycin, a greater increase in necrosis and decrease of ATP content was observed in NUPR1-defficent cells. Finally, in vivo experiments, using acute pancreatitis which induces ER stress as well as NUPR1 activation, we observed that NUPR1 expression protects acinar cells from necrosis in mice. Importantly, we also report that the cell death observed after knocking-down NUPR1 expression is completely reversed by incubation with Necrostatin-1, but not by inhibiting caspase activity with Z-VAD-FMK. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death mediated by a programmed necrosis.

16 Article Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors. 2018

Garrigue, Philippe / Tang, Jingjie / Ding, Ling / Bouhlel, Ahlem / Tintaru, Aura / Laurini, Erik / Huang, Yuanyu / Lyu, Zhenbin / Zhang, Mengjie / Fernandez, Samantha / Balasse, Laure / Lan, Wenjun / Mas, Eric / Marson, Domenico / Weng, Yuhua / Liu, Xiaoxuan / Giorgio, Suzanne / Iovanna, Juan / Pricl, Sabrina / Guillet, Benjamin / Peng, Ling. ·Aix-Marseille University, INSERM, INRA, Center de Recherche en Cardiovasculaire et Nutrition (C2VN), 13385 Marseille, France. · Aix-Marseille University, Centre Européen de Recherche en Imagerie Médicale (CERIMED), 13005 Marseille, France. · Aix-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Equipe Labellisée Ligue Contre le Cancer, 13288 Marseille, France. · Aix-Marseille University, CNRS, Institut de Chimie Radicalaire (ICR), 13013 Marseille, France. · Molecular Biology and Nanotechnology Laboratory, Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy. · Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China. · School of Life Science, Beijing Institute of Technology, Beijing 100081, China. · School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China. · Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancériologie de Marseille (CRCM), 13273 Marseille, France. · Aix-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Equipe Labellisée Ligue Contre le Cancer, 13288 Marseille, France; ling.peng@univ-amu.fr. ·Proc Natl Acad Sci U S A · Pubmed #30348798.

ABSTRACT: Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([

17 Article Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features. 2018

Puleo, Francesco / Nicolle, Rémy / Blum, Yuna / Cros, Jérôme / Marisa, Laetitia / Demetter, Pieter / Quertinmont, Eric / Svrcek, Magali / Elarouci, Nabila / Iovanna, Juan / Franchimont, Denis / Verset, Laurine / Galdon, Maria Gomez / Devière, Jacques / de Reyniès, Aurélien / Laurent-Puig, Pierre / Van Laethem, Jean-Luc / Bachet, Jean-Baptiste / Maréchal, Raphaël. ·Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: francesco.puleo@bordet.be. · Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France. · Department of Pathology, Beaujon Hospital-Paris Diderot University, Clichy, France. · Department of Pathology, Erasme Hospital, Brussels, Belgium. · Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. · Department of Pathology, Saint-Antoine Hospital, Paris, France. · Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France. · Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. · Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. · Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. · Université Paris Descartes UMRS-1147; Assistance Publique Hopitaux de Paris Hopital Européen Georges Pompidou, Paris, France. · Sorbonne Universités, UPMC Université, Department of Gastroenterology, Pitié-Salpetriére Hospital, Paris, France. ·Gastroenterology · Pubmed #30165049.

ABSTRACT: BACKGROUND & AIMS: Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. METHODS: We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts. RESULTS: We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue). CONCLUSIONS: We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

18 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 --

19 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.

20 Article LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker. 2018

Bressy, Christian / Lac, Sophie / Nigri, Jérémy / Leca, Julie / Roques, Julie / Lavaut, Marie-Nöelle / Secq, Véronique / Guillaumond, Fabienne / Bui, Thi-Thien / Pietrasz, Daniel / Granjeaud, Samuel / Bachet, Jean-Baptiste / Ouaissi, Mehdi / Iovanna, Juan / Vasseur, Sophie / Tomasini, Richard. ·CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France. · Department of Pathology, Hospital North and Mediterranean University, Marseille, France. · INSERM UMRS 775, University PARIS DESCARTES, Paris, France. · Department of Hepatobiliary and Digestive Surgery, Groupe Hospitalier Pitié Salpêtrière, Paris, France. · Department of Hepatogastroentérology, Groupe Hospitalier Pitié Salpêtrière, Paris, France. · Aix-Marseille University, INSERM, CRO2, UMR 911, Marseille, France. · CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France. richard.tomasini@inserm.fr. ·Cancer Res · Pubmed #29269518.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell-promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression.

21 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.

22 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.

23 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.

24 Article Resectable pancreatic head adenocarcinoma: Is R0 resection an illusion? Genetic evaluation of venous resection margin affirmed unrecognized disease. 2017

Turrini, O / Gilabert, M / Ewald, J / Moutardier, V / Delpero, J-R / Iovanna, J-L. ·Department of Surgical Oncology, institut Paoli-Calmettes, 13009 Marseille, France; Inserm U1068, Parc scientifique de Luminy, université de la Méditerranée, 13009 Marseille, France. Electronic address: turrinio@ipc.marseille.fr. · Department of Medical Oncology, institut Paoli-Calmettes, 13009 Marseille, France; Inserm U1068, Parc scientifique de Luminy, université de la Méditerranée, 13009 Marseille, France. · Department of Surgical Oncology, institut Paoli-Calmettes, 13009 Marseille, France. · Department of Digestive Surgery, hôpital Nord, 13015 Marseille, France. · Inserm U1068, Parc scientifique de Luminy, université de la Méditerranée, 13009 Marseille, France. ·J Visc Surg · Pubmed #28844705.

ABSTRACT: PURPOSE: To assess the K-ras gene mutation in the histologically negative venous margin of a pancreaticoduodenectomy (PD) specimen and its impact on survival. METHOD: From 2007 to 2010, 22 patients underwent R0 PD for resecable pancreatic adenocarcinoma. All specimens were stained and the portal vein (PV) bed was identified by blue ink; a 2mm RESULTS: The two groups were comparable. Overall 3years survival of patients of kras+ group versus patients of kras- group was 0 and 17% (P=0.03), respectively. Median survival time of patients of kras+ group versus patients of kras- group was 16months vs 25months (P=0.04; 95% confidence interval [1,11-1,88]), respectively. CONCLUSION: Genetic evaluation of venous resection margin affirmed unrecognized disease with strong impact on survival in more than 50% of patients with histologically R0 resection.

25 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.

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