Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Marlène Dufresne
Based on 15 articles published since 2010
(Why 15 articles?)
||||

Between 2010 and 2020, M. Dufresne wrote the following 15 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review [Advance in the biology of pancreatic of cancer]. 2015

Buscail, Louis / Bournet, Barbara / Dufresne, Marlène / Torrisani, Jérôme / Cordelier, Pierre. ·Inserm UMR 1037, Centre de recherche en cancérologie de Toulouse 2, avenue Hubert-Curien, Oncopole de Toulouse, CS 53717, 31037 Toulouse cedex 1. Electronic address: Buscail.L@chu-toulouse.fr. · Inserm UMR 1037, Centre de recherche en cancérologie de Toulouse 2, avenue Hubert-Curien, Oncopole de Toulouse, CS 53717, 31037 Toulouse cedex 1. ·Bull Cancer · Pubmed #26118878.

ABSTRACT: The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic/epigenetic alterations and molecular expression in experimental models as well as precancerous and cancerous tissues by mean of molecular amplification and large-scale transcriptoma analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating point mutation of the KRAS oncogene on codon 12 is the major event and occurs early in pancreatic carcinogenesis. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, Nerve Growth Factor, gastrin), of pro-angiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, tissue plasminogen activators) occurs. The microenvironment plays also a key role in the invasive and metastatic process of pancreatic carcinoma with a strong relationship between cancerous cells and pancreatic stellate cells as well as extracellular matrix. This microenvironment strongly participates to the tumor fibrosis, hypoxia and hypovascularization inducing an inaccessibility of drugs. Nowadays, the targeting of microenvironment takes a special place in the new therapeutic strategies of pancreatic cancer in combination with chemotherapy.

2 Review MicroRNAs as emerging biomarkers and therapeutic targets for pancreatic cancer. 2014

Gayral, Marion / Jo, Sébastien / Hanoun, Naima / Vignolle-Vidoni, Alix / Lulka, Hubert / Delpu, Yannick / Meulle, Aline / Dufresne, Marlène / Humeau, Marine / Chalret du Rieu, Maël / Bournet, Barbara / Sèlves, Janick / Guimbaud, Rosine / Carrère, Nicolas / Buscail, Louis / Torrisani, Jérôme / Cordelier, Pierre. ·Marion Gayral, Sébastien Jo, Naima Hanoun, Alix Vignolle-Vidoni, Hubert Lulka, Yannick Delpu, Aline Meulle, Marlène Dufresne, Marine Humeau, Maël Chalret du Rieu, Barbara Bournet, Janick Sèlves, Rosine Guimbaud, Nicolas Carrère, Louis Buscail, Jérôme Torrisani, Pierre Cordelier, Cancer Research Center of Toulouse Team 10, UMR INSERM U1037, Université Paul Sabatier, 31100 Toulouse, France. ·World J Gastroenterol · Pubmed #25170204.

ABSTRACT: Despite tremendous efforts from scientists and clinicians worldwide, pancreatic adenocarcinoma (PDAC) remains a deadly disease due to the lack of early diagnostic tools and reliable therapeutic approaches. Consequently, a majority of patients (80%) display an advanced disease that results in a low resection rate leading to an overall median survival of less than 6 months. Accordingly, robust markers for the early diagnosis and prognosis of pancreatic cancer, or markers indicative of survival and/or metastatic disease are desperately needed to help alleviate the dismal prognosis of this cancer. In addition, the discovery of new therapeutic targets is mandatory to design effective treatments. In this review, we will highlight the translational studies demonstrating that microRNAs may soon translate into clinical applications as long-awaited screening tools and therapeutic targets for PDAC.

3 Review [Kras oncogene and pancreatic cancer: thirty years after]. 2013

Bournet, Barbara / Dufresne, Marlène / Selves, Janick / Torrisani, Jérôme / Cordelier, Pierre / Buscail, Louis. ·Inserm UMR U1037, Centre de recherche sur le cancer de Toulouse, CHU Rangueil, 1, avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France - Service de gastroentérologie et nutrition, CHU Rangueil-Larrey, 1, avenue Jean Poulhès, TSA 50032, 31059 Toulouse, Cedex 9, France. ·Med Sci (Paris) · Pubmed #24280502.

ABSTRACT: Point mutations of the Kras oncogene induce in cancerous cells an uncontrolled increase of cell proliferation and invasiveness. Mutation of Kras appears early during the process of the pancreatic carcinogenesis and is the most frequent genetic alteration in pancreatic adenocarcinoma (75 to 95 % of cases) as well as in precancerous lesions such as PanIN and IMPN. These latter lesions and tumour microenvironment are reproduced in transgenic models developed in mice. These models are induced on the basis of Kras mutation (Pdx1-Cre ; Kras(G12D) mice) associated or not to the inactivation of tumour suppressor genes (TP53, DPC4, INK4A). Kras mutation assay is easily performed in human biological samples, especially in the cellular material sampled in pancreatic masses under endoscopic ultrasound by fine needle aspiration biopsy. In the near future, searching for Kras mutation could be useful in clinical practice either for positive diagnosis of pancreatic adenocarcinoma in case of unconclusive/doubtful cytopathological analysis or for the differential diagnosis with chronic pancreatitis especially in its pseudotumoural form.

4 Clinical Trial First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings. 2015

Buscail, Louis / Bournet, Barbara / Vernejoul, Fabienne / Cambois, Gilles / Lulka, Hubert / Hanoun, Naïma / Dufresne, Marlène / Meulle, Aline / Vignolle-Vidoni, Alix / Ligat, Laetitia / Saint-Laurent, Nathalie / Pont, Frédéric / Dejean, Sébastien / Gayral, Marion / Martins, Frédéric / Torrisani, Jérôme / Barbey, Odile / Gross, Fabian / Guimbaud, Rosine / Otal, Philippe / Lopez, Frédéric / Tiraby, Gérard / Cordelier, Pierre. ·1] Department of Gastroenterology, CHU Toulouse - Rangueil, Toulouse, France [2] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 CRCT, Toulouse, France [4] CIC Biotherapies 511, CHU Toulouse and INSERM, Toulouse, France. · 1] Department of Gastroenterology, CHU Toulouse - Rangueil, Toulouse, France [2] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 CRCT, Toulouse, France. · Cayla InvivoGen Company, Research Department, Toulouse, France. · 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France. · 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 Proteomic Group-CRCT, Toulouse, France. · Department of Mathematics, Université Toulouse III-Paul Sabatier, Toulouse, France. · Inserm, UMR1048, Toulouse, France. · CIC Biotherapies 511, CHU Toulouse and INSERM, Toulouse, France. · 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France [3] Department of Oncology, CHU Toulouse-Rangueil, Toulouse, France. · 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Department of Radiology, CHU Toulouse-Rangueil, Toulouse, France. ·Mol Ther · Pubmed #25586689.

ABSTRACT: This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.

5 Article Experimental pancreatic cancer develops in soft pancreas: novel leads for an individualized diagnosis by ultrafast elasticity imaging. 2019

Therville, Nicole / Arcucci, Silvia / Vertut, Aurélie / Ramos-Delgado, Fernanda / Da Mota, Dina Ferreira / Dufresne, Marlène / Basset, Céline / Guillermet-Guibert, Julie. ·INSERM U1037, CRCT, Université Paul Sabatier, Toulouse. · Laboratoire d'Excellence TouCAN. · Laboratoire d'Histologie et d'Embryologie, Faculté de médecine de Rangueil, Toulouse. · Service d'Anatomo-Pathologie, IUCT-O, Toulouse. ·Theranostics · Pubmed #31588223.

ABSTRACT: Rapid, easy and early pancreatic cancer diagnosis and therapeutic follow up continue to necessitate an increasing attention towards the development of effective treatment strategies for this lethal disease. The non invasive quantitative assessment of pancreatic heterogeneity is limited. Here, we report the development of a preclinical imaging protocol using ultrasonography and shear wave technology in an experimental in situ pancreatic cancer model to measure the evolution of pancreatic rigidity.

6 Article Pancreatic preneoplastic lesions plasma signatures and biomarkers based on proteome profiling of mouse models. 2015

Ligat, Laetitia / Saint-Laurent, Nathalie / El-Mrani, Aïcha / Gigoux, Véronique / Al Saati, Talal / Tomasini, Richard / Nigri, Jérémy / Dejean, Sébastien / Pont, Frédéric / Baer, Romain / Guillermet-Guibert, Julie / Cordelier, Pierre / Lopez, Frédéric / Dufresne, Marlène. ·Proteomics Group, Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR1037, Université Toulouse III-Paul Sabatier, Toulouse 31037, France. · EA 4552, Université Toulouse III-Paul Sabatier, Toulouse 31432, France. · INSERM-US006 ANEXPLO/CREFRE-Histology facility, Toulouse 31024, France. · Centre de Recherches en Cancérologie de Marseille (CRCM), Inserm U1068, Institut Paoli-Calmettes, Université Aix-Marseille, CNRS, UMR7258, Marseille 13288, France. · Institut de Mathématiques de Toulouse, UMR 5219 CNRS, Université Toulouse III-Paul Sabatier, Toulouse 31062, France. · Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR1037, Université Toulouse III-Paul Sabatier, Equipe Labellisée Ligue Contre le Cancer, Toulouse 31037, France. · Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR1037, Université Toulouse III-Paul Sabatier, Toulouse 31037, France. ·Br J Cancer · Pubmed #26512875.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a mortality that is almost identical to incidence. Because early detected PDAC is potentially curable, blood-based biomarkers that could detect currently developing neoplasia would improve patient survival and management. PDAC develops from pancreatic intraepithelial neoplasia (PanIN) lesions, graded from low grade (PanIN1) to high grade (PanIN3). We made the hypothesis that specific proteomic signatures from each precancerous stage exist and are detectable in plasma. METHODS: We explored the peptide profiles of microdissected PanIN cells and of plasma samples corresponding to the different PanIN grade from genetically engineered mouse models of PDAC using capillary electrophoresis coupled to mass spectrometry (CE-MS) and Chip-MS/MS. RESULTS: We successfully characterised differential peptides profiles from PanIN microdissected cells. We found that plasma from tumor-bearing mice and age-matched controls exhibit discriminative peptide signatures. We also determined plasma peptide signatures corresponding to low- and high-grade precancerous step present in the mice pancreas using the two mass spectrometry technologies. Importantly, we identified biomarkers specific of PanIN3. CONCLUSIONS: We demonstrate that benign and advanced PanIN lesions display distinct plasma peptide patterns. This strongly supports the perspectives of developing a non-invasive screening test for prediction and early detection of PDAC.

7 Article Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-Induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16. 2015

Chalabi-Dchar, Mounira / Cassant-Sourdy, Stéphanie / Duluc, Camille / Fanjul, Marjorie / Lulka, Hubert / Samain, Rémi / Roche, Catherine / Breibach, Florence / Delisle, Marie-Bernadette / Poupot, Mary / Dufresne, Marlène / Shimaoka, Takeshi / Yonehara, Shin / Mathonnet, Muriel / Pyronnet, Stéphane / Bousquet, Corinne. ·INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France. · UMR7286 CNRS-Aix-Marseille University, Neurobiology and Neurophysiology Research Center of Marseille, and Laboratory of Molecular Biology, AP-HM Conception, Marseille, France. · Pathology Department, Toulouse Hospitals, Toulouse, France. · Department of Molecular Preventive Medicine, Graduate School of Medicine, Tokyo University, Tokyo, Japan. · Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan. · EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France. · INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France. Electronic address: corinne.bousquet@inserm.fr. ·Gastroenterology · Pubmed #25683115.

ABSTRACT: BACKGROUND & AIMS: The KRAS gene is mutated in most pancreatic ductal adenocarcinomas (PDAC). Expression of this KRAS oncoprotein in mice is sufficient to initiate carcinogenesis but not progression to cancer. Activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is required for KRAS for induction and maintenance of PDAC in mice. The somatostatin receptor subtype 2 (sst2) inhibits PI3K, but sst2 expression is lost during the development of human PDAC. We investigated the effects of sst2 loss during KRAS-induced PDAC development in mice. METHODS: We analyzed tumor growth in mice that expressed the oncogenic form of KRAS (KRAS(G12D)) in pancreatic precursor cells, as well as sst2+/- and sst2-/-, and in crossed KRAS(G12D);sst2+/- and KRAS(G12D);sst2-/- mice. Pancreatic tissues and acini were collected and assessed by histologic, immunoblot, immunohistochemical, and reverse-transcription polymerase chain reaction analyses. We also compared protein levels in paraffin-embedded PDAC samples from patients vs heathy pancreatic tissues from individuals without pancreatic cancer. RESULTS: In sst2+/- mice, PI3K was activated and signaled via AKT (PKB; protein kinase B); when these mice were crossed with KRAS(G12D) mice, premalignant lesions, tumors, and lymph node metastases developed more rapidly than in KRAS(G12D) mice. In crossed KRAS(G12D);sst2+/- mice, activation of PI3K signaling via AKT resulted in activation of nuclear factor-κB (NF-κB), which increased KRAS activity and its downstream pathways, promoting initiation and progression of neoplastic lesions. We found this activation loop to be mediated by PI3K-induced production of the chemokine CXCL16. Administration of a CXCL16-neutralizing antibody to KRAS(G12D) mice reduced activation of PI3K signaling to AKT and NF-κB, blocking carcinogenesis. Levels of CXCL16 and its receptor CXCR6 were significantly higher in PDAC tissues and surrounding acini than in healthy pancreatic tissues from mice or human beings. In addition, expression of sst2 was progressively lost, involving increased PI3K activity, in mouse lesions that expressed KRAS(G12D) and progressed to PDAC. CONCLUSIONS: Based on analyses of mice, loss of sst2 from pancreatic tissues activates PI3K signaling via AKT, leading to activation of NF-κB, amplification of oncogenic KRAS signaling, increased expression of CXCL16, and pancreatic tumor formation. CXCL16 might be a therapeutic target for PDAC.

8 Article Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α. 2014

Baer, Romain / Cintas, Célia / Dufresne, Marlène / Cassant-Sourdy, Stéphanie / Schönhuber, Nina / Planque, Laetitia / Lulka, Hubert / Couderc, Bettina / Bousquet, Corinne / Garmy-Susini, Barbara / Vanhaesebroeck, Bart / Pyronnet, Stéphane / Saur, Dieter / Guillermet-Guibert, Julie. ·UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France; · UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; · Department of Internal Medicine 2, Technische Universität München, 81675 Munich, Germany; · UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Inserm, F-31000 Toulouse, France; Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; · Cell Signaling, UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom; · Department of Internal Medicine 2, Technische Universität München, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ·Genes Dev · Pubmed #25452273.

ABSTRACT: Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110α PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110β, did not prevent preneoplastic lesion initiation. p110α signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110α was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110α cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110α is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment.

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

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

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

10 Article The conditional expression of KRAS G12D in mouse pancreas induces disorganization of endocrine islets prior the onset of ductal pre-cancerous lesions. 2013

Gout, Johann / Pommier, Roxane M / Vincent, David F / Ripoche, Doriane / Goddard-Léon, Sophie / Colombe, Amélie / Treilleux, Isabelle / Valcourt, Ulrich / Tomasini, Richard / Dufresne, Marlène / Bertolino, Philippe / Bartholin, Laurent. ·TGFβ and Pancreatic Cancer Laboratory, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France. ·Pancreatology · Pubmed #23719586.

ABSTRACT: BACKGROUND/OBJECTIVES: Pdx1-Cre; LSL-KRAS(G12D) mice develop premalignant pancreatic ductal lesions that can possibly progress spontaneously to pancreatic ductal adenocarcinoma (PDAC). Although Pdx1-Cre is expressed in the embryonic endoderm, which gives rise to all pancreatic lineages, the possible consequences of KRAS(G12D) expression in the endocrine compartment have never been finely explored. METHODS: We examined by histology whether Pdx1-driven expression of KRAS(G12D) could induce islets of Langerhans defects. RESULTS: We observed in Pdx1-Cre; LSL-KRAS(G12D) early disorganization of the endocrine compartment including i) hyperplasia affecting all the endocrine lineages, ii) ectopic onset of Ck19-positive (ductal-like) structures within the endocrine islets, and iii) the presence of islet cells co-expressing glucagon and insulin, all occurring before the onset of ducts lesions. CONCLUSIONS: This work indicates that expression of KRAS(G12D) in Pdx1-expressing cells during embryogenesis affects the endocrine pancreas, and highlights the need to deepen possible consequences on both glucose metabolism and PDAC initiation.

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

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

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

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

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

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

13 Article Id3 modulates cellular localization of bHLH Ptf1-p48 protein. 2011

Dufresne, Marlène / Clerc, Pascal / Dieng, Madieng / Edir, Anissa / Couvelard, Anne / Delisle, Marie-Bernadette / Fourmy, Daniel / Gigoux, Véronique. ·Inserm U858, F-31432 Toulouse, France. ·Int J Cancer · Pubmed #20830706.

ABSTRACT: Ptf1-p48 is a pancreas-specific bHLH transcriptional protein, which, in the normal adult pancreas, shows a restricted expression in acinar cells where it is predominantly localized in the nucleus and activates the transcription of exocrine-specific genes. Ptf1-p48 partners with two proteins to form the PTF1 active complex: a bHLH E-protein and suppressor of hairless RBP-J. Cytoplasmic mislocalization of Ptf1-p48 has been reported in pancreatic pathologies, suggesting its contribution in the early steps of pancreatic carcinogenesis. The aim of the our work was to elucidate the mechanisms regulating Ptf1-p48 subcellular localization. We hypothesized a role of Id proteins acting in a dominant-negative fashion by heterodimerizing with bHLH proteins. We reproduced Ptf1-p48 cytoplasmic mislocalization in acinar AR4-2J cells and demonstrated that a proliferative signal elicited by gastrin leads to increases in Id3 protein expression and levels of Id3/E47 and Id3/Ptf1-p48 interactions, and a decrease in the level of E47/Ptf1-p48 interaction. By contrast, Id3 silencing reversed the cytoplasmic mislocalization of Ptf1-p48 induced by gastrin. As E47 is responsible for the nuclear import of the PTF1 complex, disruption of this complex via Id3 interactions with both E47 and Ptf1-p48 appears to induce cytoplasmic mislocalization of Ptf1-p48. We then found that Ptf1-p48 is either absent or mislocalized in the cytoplasm and Id3 is overexpressed in human and murine pancreatic preneoplastic lesions. Our data provide novel insight into the regulation of Ptf1-p48 function and provide evidence that Ptf1-p48 cytoplasmic mislocalization and Id3 overexpression are early events in pancreatic cancer progression.

14 Article The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis. 2010

Hanoun, Naïma / Delpu, Yannick / Suriawinata, Arief A / Bournet, Barbara / Bureau, Christophe / Selves, Janick / Tsongalis, Gregory J / Dufresne, Marlène / Buscail, Louis / Cordelier, Pierre / Torrisani, Jérôme. ·INSERM, U858, Toulouse, France. ·Clin Chem · Pubmed #20431052.

ABSTRACT: BACKGROUND: The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is accounted for by the absence of early diagnostic markers and effective treatments. MicroRNAs inhibit the translation of their target mRNAs. The production of microRNAs is strongly altered in cancers, but the causes of these alterations are only partially known. DNA hypermethylation is a major cause of gene inactivation in cancer. Our aims were to identify microRNAs whose gene expression is inactivated by hypermethylation in PDAC and to determine whether this hypermethylation-mediated repression is an early event during pancreatic carcinogenesis. We also sought to investigate whether these differentially methylated regions can serve as a diagnostic marker for PDAC. METHODS: MicroRNA production was measured by microarray hybridization and reverse-transcription quantitative PCR. The level of DNA methylation was measured by bisulfite mapping and semiquantitative methylation-specific PCR. RESULTS: We identified 29 microRNAs encoded by genes whose expression is potentially inactivated by DNA hypermethylation. We focused our study on microRNA 148a (miR-148a) and found its production to be repressed, not only in PDAC samples but also in preneoplastic pancreatic intraepithelial neoplasia (PanIN) lesions. More importantly, we found that hypermethylation of the DNA region encoding miR-148a is responsible for its repression, which occurs in PanIN preneoplastic lesions. Finally, we show that the hypermethylated DNA region encoding miR-148a can serve as an ancillary marker for the differential diagnosis of PDAC and chronic pancreatitis (CP). CONCLUSIONS: We show that the hypermethylation of the DNA region encoding miR-148a is responsible for its repression in PDAC precursor lesions and can be a useful tool for the differential diagnosis of PDAC and CP.

15 Article MicroRNA-21 is induced early in pancreatic ductal adenocarcinoma precursor lesions. 2010

du Rieu, Maël Chalret / Torrisani, Jérôme / Selves, Janick / Al Saati, Talal / Souque, Anny / Dufresne, Marlène / Tsongalis, Gregory J / Suriawinata, Arief A / Carrère, Nicolas / Buscail, Louis / Cordelier, Pierre. ·INSERM, U858, Institut de Médecine Moléculaire de Rangueil (I2MR), Université Toulouse III Paul Sabatier IFR150, Toulouse, France. ·Clin Chem · Pubmed #20093556.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has the poorest overall prognosis among gastrointestinal cancers; however, curative resection in early-stage PDAC greatly improves survival rates, indicating the importance of early detection. Because abnormal microRNA production is commonly detected in cancer, we investigated noninvasive precursor pancreatic intraepithelial neoplasia (PanIN) lesions for microRNA production as a potential early biomarker of PDAC. METHODS: Pathologists identified and classified ductal lesions. We extracted total RNA from laser-capture microdissected PanIN tissue samples from a conditional KRAS(G12D) mouse model (n = 29) or of human origin (n = 38) (KRAS is v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). MicroRNA production was quantified by quantitative real-time PCR. Internal controls included 5S and U6 RNAs. RESULTS: Production of microRNAs miR-21, miR-205, and miR-200 paralleled PanIN progression in the KRAS(G12D) mouse model, compared with microRNA production in samples of nonpathologic ducts. miR-21 demonstrated the highest relative concentrations in the precursor lesions. Interestingly, miR-205 and miR-21 up-regulation preceded phenotypic changes in the ducts. The production of microRNAs miR-21, miR-221, miR-222, and let-7a increased with human PanIN grade, with peak production occurring in hyperplastic PanIN-2/3 lesions. In situ hybridization analysis indicated miR-21 production to be concentrated in pathologic ductal cells. miR-21 production was regulated by KRAS(G12D) and epidermal growth factor receptor in PDAC-derived cell lines. CONCLUSIONS: Aberrant microRNA production is an early event in the development of PanIN. Our findings indicate that miR-21 warrants further investigation as a marker for early detection of PDAC.