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Pancreatic Neoplasms: HELP
Articles by Juan Lucio Iovanna
Based on 84 articles published since 2010
(Why 84 articles?)
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Between 2010 and 2020, J. Iovanna wrote the following 84 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 / Anonymous1151075. ·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 Upcoming Revolutionary Paths in Preclinical Modeling of Pancreatic Adenocarcinoma. 2019

Swayden, Mirna / 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. ·Front Oncol · Pubmed #32038993.

ABSTRACT: To date, PDAC remains the cancer having the worst prognosis with mortality rates constantly on the rise. Efficient cures are still absent, despite all attempts to understand the aggressive physiopathology underlying this disease. A major stumbling block is the outdated preclinical modeling strategies applied in assessing effectiveness of novel anticancer therapeutics. Current

5 Review Emerging epigenomic landscapes of pancreatic cancer in the era of precision medicine. 2019

Lomberk, Gwen / Dusetti, Nelson / Iovanna, Juan / Urrutia, Raul. ·Division of Research, Department of Surgery and the Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA. glomberk@mcw.edu. · 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, 13288, Marseille, France. · Division of Research, Department of Surgery and the Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA. rurrutia@mcw.edu. ·Nat Commun · Pubmed #31462645.

ABSTRACT: Genetic studies have advanced our understanding of pancreatic cancer at a mechanistic and translational level. Genetic concepts and tools are increasingly starting to be applied to clinical practice, in particular for precision medicine efforts. However, epigenomics is rapidly emerging as a promising conceptual and methodological paradigm for advancing the knowledge of this disease. More importantly, recent studies have uncovered potentially actionable pathways, which support the prediction that future trials for pancreatic cancer will involve the vigorous testing of epigenomic therapeutics. Thus, epigenomics promises to generate a significant amount of new knowledge of both biological and medical importance.

6 Review Pancreatic Cancer Heterogeneity Can Be Explained Beyond the Genome. 2019

Juiz, Natalia Anahi / Iovanna, Juan / Dusetti, Nelson. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France. ·Front Oncol · Pubmed #31024848.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a major health problem because it induces almost systematic mortality. Carcinogenesis begins with genetic aberrations which trigger epigenetic modifications. While genetic mutations initiate tumorigenesis, they are unable to explain the vast heterogeneity observed among PDAC patients. Instead, epigenetic changes drive transcriptomic alterations that can regulate the malignant phenotype. The contribution of factors from the environment and tumor microenvironment defines different epigenetic landscapes that outline two clinical subtypes: basal, with the worst prognosis, and classical. The epigenetic nature of PDAC, as a reversible phenomenon, encouraged several studies to test epidrugs. However, these drugs lack specificity and although there are epigenetic patterns shared by all PDAC tumors, there are others that are specific to each subtype. Molecular characterization of the epigenetic mechanisms underlying PDAC heterogeneity could be an invaluable tool to predict personalized therapies, stratify patients and search for novel therapies with more specific phenotype-based targets. Novel therapeutic strategies using current anticancer compounds or existing drugs used in other pathologies, alone or in combination, could be used to kill tumor cells or convert aggressive tumors into a more benign phenotype.

7 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.

8 Review Factors released by the tumor far microenvironment are decisive for pancreatic adenocarcinoma development and progression. 2017

Iovanna, Juan L / Closa, Daniel. ·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. · Department of Experimental Pathology, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. ·Oncoimmunology · Pubmed #29147622.

ABSTRACT: The REG3β protein was identified more than 2 decades ago, but its role in PDAC development was only recently reported. In Pancreatic Ductal Adenocarcinoma (PDAC), REG3β protein is expressed and released by the far microenvironment, which is situated out of the tumor, at the periphery of the tumor mass, and is part of the healthy peri-tumoral region. This compartment is completely unrelated to the classical microenvironment that corresponds to the intra-tumoral stoma. Clinically relevant, the far microenvironment, and the factors released by it, could be novel and original therapeutic targets for treating patients with a PDAC. In this way we recently demonstrated that REG3β is an essential soluble factor necessary for PDAC development which is able to stimulate several simultaneous pro-tumoral mechanisms. We also find that secreted REG3β boosts interactions between epithelial cells and immune cells by activating the CXCL12/CXCR4 signaling cascade, which facilitates tumor escape through evasion of immune surveillance, and promotes metastasis. In addition, REG3β interfere the intercellular communication inside the tumor mediated by extracellular vesicles, resulting in relevant changes in macrophage phenotype or tumor cell migration. Therefore, we are proposing to call as near microenvironment to the classical microenvironment that is constituted by fibroblasts, inflammatory cells and fibers and located into the tumor, and as far microenvironment, which is constituted by the parenchymal non transformed cells located at the periphery of the tumor mass.

9 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.

10 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.

11 Review Autophagy Induced during Pancreatitis Promotes 2016

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 , Marseille , France. ·Front Oncol · Pubmed #27833900.

ABSTRACT: Pancreatitis is an inflammatory disease that both facilitates and accelerates the transformation of pancreatic cells upon activation of the

12 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.

13 Review Pancreatitis promotes oncogenic Kras(G12D)-induced pancreatic transformation through activation of Nupr1. 2014

Grasso, Daniel / Garcia, Maria Noé / Hamidi, Tewfik / Cano, Carla / Calvo, Ezequiel / Lomberk, Gwen / Urrutia, Raul / Iovanna, Juan L. ·Centre de Recherche en Cancérologie de Marseille (CRCM); Aix-Marseille Université and Institut Paoli-Calmettes; Parc Scientifique et Technologique de Luminy; Marseille, France. · Molecular Endocrinology and Oncology Research Center; CHUL Research Center; Quebec, QC Canada. · Laboratory of Epigenetics and Chromatin Dynamics; Gastroenterology Research Unit; Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Mayo Clinic; Rochester, MA USA. ·Mol Cell Oncol · Pubmed #27308320.

ABSTRACT: During the initiation stage of pancreatic adenocarcinoma induced by oncogenic Kras, pancreatic cells are exposed to both a protumoral effect and an opposing tumor suppressive process known as oncogene-induced senescence. Pancreatitis disrupts this balance in favor of the transforming effect of oncogenes by lowering the tumor suppressive threshold of oncogene-induced senescence through expression of the stress protein Nupr1.

14 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.

15 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.

16 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.

17 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.

18 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.

19 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.

20 Article Deciphering the Crosstalk Between Myeloid-Derived Suppressor Cells and Regulatory T Cells in Pancreatic Ductal Adenocarcinoma. 2019

Siret, Carole / Collignon, Aurélie / Silvy, Françoise / Robert, Stéphane / Cheyrol, Thierry / André, Perrine / Rigot, Véronique / Iovanna, Juan / van de Pavert, Serge / Lombardo, Dominique / Mas, Eric / Martirosyan, Anna. ·Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France. · Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Marseille, France. · Aix Marseille Univ, INSERM, VRCM, Centre de Recherche Vasculaire de Marseille, Marseille, France. · Aix Marseille Univ, CEFOS, Centre d'exploration Fonctionnelle Scientifique, Marseille, France. · Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Centre de Recherche en Cancérologie de Marseille, Marseille, France. ·Front Immunol · Pubmed #32038621.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with rising incidence and a remarkable resistance to current therapies. The reasons for this therapeutic failure include the tumor's extensive infiltration by immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). By using light sheet fluorescent microscopy, we identified here direct interactions between these major immunoregulatory cells in PDAC. The

21 Article Pancreatic Cancer Organoids for Determining Sensitivity to Bromodomain and Extra-Terminal Inhibitors (BETi). 2019

Bian, Benjamin / Juiz, Natalia Anahi / Gayet, Odile / Bigonnet, Martin / Brandone, Nicolas / Roques, Julie / Cros, Jérôme / Wang, Nenghui / 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. · Pathology Department, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, UMR 1149, Inflammation Research Center, INSERM - Paris Diderot University, Paris, France. · Ningbo Wenda Pharma Technology Ltd., Zhejiang, China. ·Front Oncol · Pubmed #31231611.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease, therefore stratification of patients is essential to predict their responses to therapies and to choose the best treatment. PDAC-derived organoids were produced from PDTX and Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) biopsies. A signature based on 16 genes targets of the c-MYC oncogene was applied to classify samples into two sub-groups with distinctive phenotypes named MYC-high and MYC-low. The analysis of 9 PDTXs and the corresponding derived organoids revealed that this signature which was previously designed from PDTX is transferable to the organoid model. Primary organoids from 24 PDAC patients were treated with NHWD-870 or JQ1, two inhibitors of c-MYC transcription. Notably, the comparison of their effect between the two sub-groups showed that both compounds are more efficient in MYC-high than in MYC-low samples, being NHWD-870 the more potent treatment. In conclusion, this study shows that the molecular signatures could be applied to organoids obtained directly from PDAC patients to predict the treatment response and could help to take the more appropriate therapeutic decision for each patient in a clinical timeframe.

22 Article Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF. 2019

Blasco, María Teresa / Navas, Carolina / Martín-Serrano, Guillermo / Graña-Castro, Osvaldo / Lechuga, Carmen G / Martín-Díaz, Laura / Djurec, Magdolna / Li, Jing / Morales-Cacho, Lucia / Esteban-Burgos, Laura / Perales-Patón, Javier / Bousquet-Mur, Emilie / Castellano, Eva / Jacob, Harrys K C / Cabras, Lavinia / Musteanu, Monica / Drosten, Matthias / Ortega, Sagrario / Mulero, Francisca / Sainz, Bruno / Dusetti, Nelson / Iovanna, Juan / Sánchez-Bueno, Francisco / Hidalgo, Manuel / Khiabanian, Hossein / Rabadán, Raul / Al-Shahrour, Fátima / Guerra, Carmen / Barbacid, Mariano. ·Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain. · Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain. · Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain. · Transgenic Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain. · Molecular Imaging Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain. · Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry, School of Medicine, Autonomous University of Madrid, 28018 Madrid, Spain. · 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. · Department of Surgery, Clinical University Hospital 'Virgen Arrixaca' - Murcian Institute of Biomedical Investigation (IMIB), 30120 Murcia, Spain. · Rosenberg Clinical Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. · Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain. Electronic address: mcguerra@cnio.es. · Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain. Electronic address: mbarbacid@cnio.es. ·Cancer Cell · Pubmed #30975481.

ABSTRACT: Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.

23 Article Prognostic significance of circulating PD-1, PD-L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma. 2019

Bian, Benjamin / Fanale, Daniele / Dusetti, Nelson / Roque, Julie / Pastor, Sonia / Chretien, Anne-Sophie / Incorvaia, Lorena / Russo, Antonio / Olive, Daniel / Iovanna, Juan. ·Team Pancreatic Cancer, 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. · Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy. · Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France. ·Oncoimmunology · Pubmed #30906655.

ABSTRACT: PDAC is one of the most heterogeneous cancers with low chemotherapeutic sensitivity due to a dense stroma, a weak vasculature and significant biological aggressivity. In cancer, suppressive immune checkpoints are often hyper-activated to ensure an effective evasion of tumor cells from immune surveillance. These immune checkpoints include in part, the B7/butyrophilin-like receptors such as butyrophilin sub-family 3A/CD277 receptors (BTN3A), the B and T lymphocyte attenuator (BTLA) belonging to the B7-like receptors and the programmed death protein (PD-1) with its ligand PD-L1. We evaluated the plasma level of these markers in 32 PDAC patients (learning cohort) by

24 Article Ribonuclease MCPiP1 contributes to the loss of micro-RNA-200 family members in pancreatic cancer cells. 2018

Boudouresque, Françoise / Siret, Carole / Dobric, Aurélie / Silvy, Françoise / Soubeyran, Philippe / Iovanna, Juan / Lombardo, Dominique / Berthois, Yolande. ·Aix-Marseille Univ, INSERM UMR 911, CRO2, Marseille, France. · Aix-Marseille Univ, CNRS, INSERM, CIML Marseille, France. · Present address: Aix-Marseille University, INSERM, CNRS, Institut Paoli-Calmettes, CRCM, Pancreatic Cancer Team, Marseille, France. ·Oncotarget · Pubmed #30542509.

ABSTRACT: The microRNA-200 (miR-200) family is frequently down-regulated in tumors, including pancreatic adenocarcinomas (PDACs). In this study we have examined the mechanisms involved in the loss of miR-200s in tumoral pancreatic cells. Whereas miR-200 gene promoters appear methylated in mature miR-200 deficient cell lines, miR-200 precursors are detected in nuclear but not cytoplasmic compartment of these cells, indicating that promoter hypermethylation is not sufficient to explain the deficit of mature miR-200s. The ribonuclease Monocyte Chemotactic Protein-induced Protein-1 (MCPiP1) may counteract Dicer1 in miRNA maturation process. MCPiP1/Dicer1 mRNA and protein ratios appear higher in miR-200 deficient compared to miR-200 proficient cells, suggesting that MCPiP1 may compete with Dicer1 in mature miR-200 deficient cells. Inhibition of MCPiP1 allows the detection of miR-200 precursors in cytoplasm of miR-200 deficient cells, confirming its involvement in the loss of miR-200s. Also, reversion of MCPiP1/Dicer1 ratio by over-expression of Dicer1 in miR-200 deficient cells leads to the recovery of mature miR-200s. Finally, whereas human malignant pancreatic tissues (PDACs) express lower miR-200 levels than non malignant tissues (non-MPDs), MCPiP1/Dicer1 ratio appears higher in PDACs, when compared to non-MPDs, supporting the hypothesis that MCPiP1/Dicer1 ratio is determinant in regulating miR-200 maturation process in a subset of tumoral pancreatic cells.

25 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.

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