, Cancer Facts & Figures, 2013.

. Burris, . Moore, . Mj, J. Andersen, . Green et al., Improvements in survival and clinical benefit with gemcitabine as firstline therapy for patients with advanced pancreas cancer: a randomized trial, J Clin Oncol, vol.15, pp.2403-2413, 1997.

, Pancreatic Cancer Action Network

M. J. Moore, D. Goldstein, J. Hamm, A. Figer, . Hecht et al., Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group, J Clin Oncol, vol.25, pp.1960-1966, 2007.

V. Hoff, . Dd, T. Ervin, . Arena, . Fp et al., Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N Engl J Med, vol.369, pp.1691-1703, 2013.

L. Buscail, N. Saint-laurent, E. Chastre, J. C. Vaillant, C. Gespach et al., Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer, Cancer Res, vol.56, pp.1823-1827, 1996.

N. Carrere, F. Vernejoul, A. Souque, A. Asnacios, N. Vaysse et al., Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells, Hum Gene Ther, vol.16, pp.1175-1193, 2005.

F. Vernejoul, P. Faure, N. Benali, D. Calise, G. Tiraby et al., Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models, Cancer Res, vol.62, pp.6124-6131, 2002.

P. Rochaix, N. Delesque, J. P. Estève, N. Saint-laurent, J. J. Voight et al., Gene therapy for pancreatic carcinoma: local and distant antitumor effects after somatostatin receptor sst2 gene transfer, Hum Gene Ther, vol.10, pp.995-1008, 1999.

P. Cordelier, C. Bienvenu, H. Lulka, F. Marrache, M. Bouisson et al., Replication-deficient rSV40 mediate pancreatic gene transfer and long-term inhibition of tumor growth, Cancer Gene Ther, vol.14, pp.19-29, 2007.

N. Delesque, L. Buscail, J. P. Estève, N. Saint-laurent, C. Müller et al., sst2 somatostatin receptor expression reverses tumorigenicity of human pancreatic cancer cells, Cancer Res, vol.57, pp.956-962, 1997.

J. Guillermet, N. Saint-laurent, P. Rochaix, O. Cuvillier, T. Levade et al., Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis, Proc Natl Acad Sci, vol.100, pp.155-160, 2003.

N. Benali, P. Cordelier, D. Calise, P. Pages, P. Rochaix et al., Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238, Proc Natl Acad Sci, vol.97, pp.9180-9185, 2000.

S. Ohhashi, K. Ohuchida, K. Mizumoto, H. Fujita, T. Egami et al., , 2008.

, Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer, Anticancer Res, vol.28, pp.2205-2212

R. Maréchal, . Bachet, . Jb, J. R. Mackey, C. Dalban et al., Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma, Gastroenterology, vol.143, pp.664-674, 2012.

F. Vernejoul, L. Ghénassia, A. Souque, H. Lulka, D. Drocourt et al., Gene therapy based on gemcitabine chemosensitization suppresses pancreatic tumor growth, Mol Ther, vol.14, pp.758-767, 2006.

R. Siegel and . Naishadham, Cancer statistics, vol.63, pp.11-30, 2013.

S. Yachida, S. Jones, . Bozic, R. Leary, and B. Fu, Distant metastasis occurs late during the genetic evolution of pancreatic cancer, Nature, vol.467, pp.1114-1117, 2010.

S. Jones, X. Zhang, . Parsons, . Dw, J. C. Lin et al., Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science, vol.321, pp.1801-1806, 2008.

R. Siegel and D. Naishadham, Cancer statistics, CA Cancer J Clin, vol.63, pp.11-30, 2013.

H. A. Burris, M. J. Moore, and J. Andersen, Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial, J Clin Oncol, vol.15, pp.2403-2413, 1997.

M. J. Moore, D. Goldstein, and J. Hamm, Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group, J Clin Oncol, vol.25, pp.1960-1966, 2007.

T. Conroy, F. Desseigne, and M. Ychou, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N Engl J Med, vol.364, pp.1817-1825, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00598658

V. Hoff, D. D. Ervin, T. Arena, and F. P. , Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N Engl J Med, vol.369, pp.1691-1703, 2013.

C. S. Ilkow, S. L. Swift, and J. C. Bell, From scourge to cure: tumour-selective viral pathogenesis as a new strategy against cancer, PLoS Pathog, vol.10, p.1003836, 2014.

S. Jones, R. H. Hruban, and M. Kamiyama, Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene, Science, vol.324, p.217, 2009.

S. Yachida, S. Jones, and I. Bozic, Distant metastasis occurs late during the genetic evolution of pancreatic cancer, Nature, vol.467, pp.1114-1126, 2010.

Y. Touchefeu, K. Harrington, and J. Galmiche, Review article: gene therapy, recent developments and future prospects in gastrointestinal oncology, Aliment Pharmacol Ther, vol.32, pp.953-968, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00565917

S. Wennier, S. Li, and G. Mcfadden, Oncolytic virotherapy for pancreatic cancer, Expert Rev Mol Med, vol.13, p.18, 2011.

C. Xu, H. Li, and C. Su, Viral therapy for pancreatic cancer: tackle the bad guys with poison, Cancer Lett, vol.333, pp.1-8, 2013.

D. B. Gammon, B. Gowrishankar, and S. Duraffour, Vaccinia virus-encoded ribonucleotide reductase subunits are differentially required for replication and pathogenesis, PLoS Pathog, vol.6, p.1000984, 2010.

H. L. Elford, M. Freese, and E. Passamani, Ribonucleotide reductase and cell proliferation. I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas, J Biol Chem, vol.245, pp.5228-5233, 1970.

. Gayral and . Al,

L. J. Mundschau and D. V. Faller, Endogenous inhibitors of the dsRNA-dependent eIF-2 alpha protein kinase PKR in normal and ras-transformed cells, Biochimie, vol.76, pp.792-800, 1994.

H. Nakamura, H. Kasuya, and J. T. Mullen, Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5, J Clin Invest, vol.109, pp.871-882, 2002.

R. Y. Chung, Y. Saeki, and C. Ea, B-myb promoter retargeting of herpes simplex virus gamma34.5 gene-mediated virulence toward tumor and cycling cells, J Virol, vol.73, pp.7556-7564, 1999.

D. P. Eisenberg, P. S. Adusumilli, and K. J. Hendershott, 5-fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer, J Gastrointest Surg, vol.9, pp.1077-1079, 2005.

F. Sicard, M. Gayral, and H. Lulka, Targeting miR-21 for the therapy of pancreatic cancer, Mol Ther, vol.21, pp.986-994, 2013.

Y. Delpu, H. Lulka, and F. Sicard, The rescue of miR-148a expression in pancreatic cancer: an inappropriate therapeutic tool, PLoS One, vol.8, p.55513, 2013.

B. Bournet, A. Pointreau, and A. Souque, Gene expression signature of advanced pancreatic ductal adenocarcinoma using low density array on endoscopic ultrasound-guided fine needle aspiration samples, Pancreatology, vol.12, pp.27-34, 2012.

B. J. Passer, T. Cheema, and B. Zhou, Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication, Cancer Res, vol.70, pp.3890-3895, 2010.

R. Maréchal, J. Bachet, and J. R. Mackey, Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma, Gastroenterology, vol.143, pp.1-6, 2012.

N. Nakagawa, Y. Murakami, and K. Uemura, Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection, Surgery, vol.153, pp.565-575, 2013.

E. Poplin, H. Wasan, and L. Rolfe, Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity, J Clin Oncol, vol.31, pp.4453-4461, 2013.

S. Jones, X. S. Zhang, and D. W. Parsons, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science, vol.321, pp.1801-1806, 2008.

S. J. Russell, K. Peng, J. C. Bell, and . Oncolytic, Nat Biotechnol, vol.30, pp.658-670, 2012.

J. Chou, E. R. Kern, and R. J. Whitley, Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture, Science, vol.250, pp.1262-1266, 1990.

V. Rebours, M. Albuquerque, and A. Sauvanet, Hypoxia pathways and cellular stress activate pancreatic stellate cells: development of an organotypic culture model of thick slices of normal human pancreas, PLoS One, vol.8, p.76229, 2013.

Y. Kulu, H. Kawasaki, and J. M. Donahue, Concurrent chemotherapy inhibits herpes simplex virus-1 replication and oncolysis, Cancer Gene Ther, vol.20, pp.133-140, 2013.

S. Friedlander, G. C. Chu, E. L. Snyder, N. Girnius, G. Dibelius et al., Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-Ras. Cancer Cell, vol.16, pp.379-89, 2009.

T. Muniraj, P. A. Jamidar, and H. R. Aslanian, Pancreatic cancer: A comprehensive review and update, Dis Mon, vol.59, issue.11, pp.368-402, 2013.

I. Garrido-laguna and M. Hidalgo, Pancreatic cancer: from state-of-the-art treatments to promising novel therapies, Nat Rev Clin Oncol, 2015.

M. Hidalgo, Pancreatic cancer, N Engl J Med, vol.362, issue.17, pp.1605-1622, 2010.

E. H. Bruenderman and R. Martin, High-risk population in sporadic pancreatic adenocarcinoma: guidelines for screening, J Surg Res, vol.194, issue.1, pp.212-221, 2015.

D. K. Bartsch, T. M. Gress, and P. Langer, Familial pancreatic cancer--current knowledge, Nat Rev Gastroenterol Hepatol, vol.9, issue.8, pp.445-53, 2012.

M. Tanaka, F. Castillo, C. Adsay, V. Chari, S. Falconi et al., International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas, Pancreatol Off J Int Assoc Pancreatol IAP Al, vol.12, issue.3, pp.183-97, 2012.

F. M. Giardiello, S. B. Welsh, S. R. Hamilton, G. J. Offerhaus, A. M. Gittelsohn et al., Increased risk of cancer in the Peutz-Jeghers syndrome, N Engl J Med, vol.316, issue.24, pp.1511-1515, 1987.

. Vasen-h-f.-a, . Gruis-n-a, . Frants-r-r, . Van-der-velden-p-a, . Hille-e-t.-m et al., Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden), Int J Cancer, vol.87, issue.6, pp.809-820, 2000.

D. C. Whitcomb, M. C. Gorry, R. A. Preston, W. Furey, M. J. Sossenheimer et al., Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene, Nat Genet, vol.14, issue.2, pp.141-146, 1996.

M. Pelaez-luna, G. Robles-diaz, S. Canizales-quinteros, and T. Mt, PRSS1 and SPINK1 mutations in idiopathic chronic and recurrent acute pancreatitis, World J Gastroenterol WJG, vol.20, issue.33, pp.11788-92, 2014.

L. A. Torre, F. Bray, R. L. Siegel, J. Ferlay, J. Lortet-tieulent et al., Global cancer statistics, CA Cancer J Clin, 2012.

, Risk Factors Pancreatic Cancer, Pancreatic Cancer Prevention, Family History Pancreatic Cancer, Pancreas Cancer Hereditary Predisposition | Monterey

. Pancreatica, , 2015.

A. G. Renehan, M. Tyson, M. Egger, R. F. Heller, and M. Zwahlen, Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies, Lancet, vol.371, issue.9612, pp.569-78, 2008.

R. Huxley, A. Ansary-moghaddam, B. De-gonzález, A. Barzi, F. Woodward et al., Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies, Br J Cancer, vol.92, issue.11, pp.2076-83, 2005.

R. P. Sah, S. Nagpal, D. Mukhopadhyay, and S. T. Chari, New insights into pancreatic cancer-induced paraneoplastic diabetes, Nat Rev Gastroenterol Hepatol, vol.10, issue.7, pp.423-456, 2013.

Y. Delpu, N. Hanoun, H. Lulka, F. Sicard, J. Selves et al., Genetic and epigenetic alterations in pancreatic carcinogenesis, Curr Genomics, vol.12, issue.1, pp.15-24, 2011.

M. Singh and A. Maitra, Precursor lesions of pancreatic cancer: molecular pathology and clinical implications, Pancreatol Off J Int Assoc Pancreatol IAP Al, vol.7, issue.1, pp.9-19, 2007.

R. H. Hruban, A. Maitra, and M. Goggins, Update on pancreatic intraepithelial neoplasia, Int J Clin Exp Pathol, vol.1, issue.4, pp.306-322, 2008.

C. J. Scarlett, E. L. Salisbury, A. V. Biankin, and J. Kench, Precursor lesions in pancreatic cancer: morphological and molecular pathology. Pathology (Phila), vol.43, pp.183-200, 2011.

R. P. Reddy, T. C. Smyrk, M. Zapiach, M. J. Levy, R. K. Pearson et al., Pancreatic mucinous cystic neoplasm defined by ovarian stroma: demographics, clinical features, and prevalence of cancer, Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc, vol.2, issue.11, pp.1026-1057, 2004.

K. K. Roggin, J. Chennat, A. Oto, A. Noffsinger, A. Briggs et al., Pancreatic cystic neoplasm, Curr Probl Surg, vol.47, issue.6, pp.459-510, 2010.

S. Raimondi, P. Maisonneuve, and A. B. Lowenfels, Epidemiology of pancreatic cancer: an overview, Nat Rev Gastroenterol Hepatol, vol.6, issue.12, pp.699-708, 2009.

S. Pandol, A. Gukovskaya, M. Edderkoui, D. Dawson, G. Eibl et al., Epidemiology, risk factors, and the promotion of pancreatic cancer: Role of the stellate cell, J Gastroenterol Hepatol, vol.27, issue.2, pp.127-161, 2012.

S. R. Hingorani, E. F. Petricoin, A. Maitra, V. Rajapakse, C. King et al., Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse, Cancer Cell, vol.12, issue.6, pp.437-50, 2003.

Y. Matsuda, Z. Naito, K. Kawahara, N. Nakazawa, M. Korc et al., Nestin is a novel target for suppressing pancreatic cancer cell migration, invasion and metastasis, Cancer Biol Ther, vol.11, issue.5, pp.512-535, 2011.

T. Furukawa, Impacts of activation of the mitogen-activated protein kinase pathway in pancreatic cancer, Front Oncol, vol.5, p.23, 2015.

M. Kanda, H. Matthaei, J. Wu, S. Hong, J. Yu et al., Presence of Somatic Mutations in Most Early-Stage Pancreatic Intraepithelial Neoplasia, Gastroenterology, vol.142, issue.4, pp.730-733, 2012.

A. Vincent, J. Herman, R. Schulick, R. H. Hruban, and M. Goggins, Pancreatic cancer. Lancet, vol.378, pp.607-627, 2011.
URL : https://hal.archives-ouvertes.fr/hal-01429187

N. Okada, G. Ohshio, K. Yamaki, T. Imamura, and M. Imamura, Elevated Serum c-erbB-2 Protein Levels in Patients with Pancreatic Cancer: Correlation to Metastasis and Shorter Survival, Oncology, vol.52, issue.5, pp.392-398, 1995.

R. W. Cowan and A. Maitra, Genetic progression of pancreatic cancer, Cancer J Sudbury Mass, vol.20, issue.1, pp.80-84, 2014.

C. Caldas, S. A. Hahn, L. T. Da-costa, M. S. Redston, M. Schutte et al., Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma, Nat Genet, vol.8, issue.1, pp.27-32, 1994.

M. S. Redston, C. Caldas, A. B. Seymour, R. H. Hruban, L. Costa et al., p53 Mutations in Pancreatic Carcinoma and Evidence of Common Involvement of Homocopolymer Tracts in DNA Microdeletions, Cancer Res, vol.54, issue.11, pp.3025-3058, 1994.

S. A. Hahn, M. Schutte, A. T. Hoque, C. A. Moskaluk, L. T. Da-costa et al., DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, vol.271, pp.350-353, 1996.

N. Waddell, M. Pajic, A. Patch, D. K. Chang, K. S. Kassahn et al., Whole genomes redefine the mutational landscape of pancreatic cancer, Nature, vol.518, issue.7540, pp.495-501, 2015.

M. L. Gonzalgo, G. Liang, C. H. Spruck, J. M. Zingg, W. M. Rideout et al., Identification and characterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR, Cancer Res, vol.57, issue.4, pp.594-603, 1997.

B. Klump, C. J. Hsieh, O. Nehls, S. Dette, K. Holzmann et al., Methylation status of p14ARF and p16INK4a as detected in pancreatic secretions, Br J Cancer, vol.88, issue.2, pp.217-239, 2003.

T. Kuroki, Y. Tajima, and T. Kanematsu, Role of hypermethylation on carcinogenesis in the pancreas, Surg Today, vol.34, issue.12, pp.981-987, 2004.

J. M. Yi, A. A. Guzzetta, V. J. Bailey, S. R. Downing, L. Van-neste et al., Novel methylation biomarker panel for the early detection of pancreatic cancer, Clin Cancer Res Off J Am Assoc Cancer Res, vol.19, issue.23, pp.6544-55, 2013.

A. Vincent, M. Ducourouble, and I. V. Seuningen, Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases, FASEB J, vol.22, issue.8, pp.3035-3080, 2008.

M. V. Iorio and . Croce, MicroRNAs in Cancer: Small Molecules With a Huge Impact, Journal of clinical oncology, 2009.

S. Joshi, J. M. Mclendon, B. S. Comer, and W. T. Gerthoffer, MicroRNAs-control of essential genes: Implications for pulmonary vascular disease, Pulm Circ, vol.1, 2011.

Y. Huang, Y. B. Yang, X. H. Zhang, and X. L. Yu, MicroRNA-21 gene and cancer, Med Oncol, 2013.

M. C. Du-rieu, J. Torrisani, J. Selves, A. Saati, T. Souque et al., MicroRNA-21 is induced early in pancreatic ductal adenocarcinoma precursor lesions, Clin Chem, vol.56, issue.4, pp.603-615, 2010.
URL : https://hal.archives-ouvertes.fr/inserm-00480878

V. S. Nair, L. S. Maeda, and J. Ioannidis, Clinical outcome prediction by microRNAs in human cancer: a systematic review, J Natl Cancer Inst, vol.104, issue.7, pp.528-568, 2012.

M. Dillhoff, J. Liu, W. Frankel, C. Croce, and M. Bloomston, MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival, J Gastrointest Surg Off J Soc Surg Aliment Tract, vol.12, issue.12, pp.2171-2177, 2008.

J. Yu, A. Li, S. Hong, R. H. Hruban, and M. Goggins, MicroRNA alterations of pancreatic intraepithelial neoplasias, Clin Cancer Res Off J Am Assoc Cancer Res, vol.18, issue.4, pp.981-92, 2012.

C. A. Mcintyre and J. M. Winter, Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma, Semin Oncol, vol.42, issue.1, pp.19-27, 2015.

C. G. Dervenis, Pancreatic Tumors: Achievements and Perspectives. Thieme, vol.443, 2000.

A. Neesse, S. Krug, T. M. Gress, D. A. Tuveson, and P. Michl, Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma, OncoTargets Ther, vol.7, pp.33-43, 2013.

P. Michl and T. M. Gress, Current concepts and novel targets in advanced pancreatic cancer, Gut, vol.62, issue.2, pp.317-343, 2013.

H. A. Burris, M. J. Moore, J. Andersen, M. R. Green, M. L. Rothenberg et al., Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial, J Clin Oncol Off J Am Soc Clin Oncol, vol.15, issue.6, pp.2403-2416, 1997.

M. Barton-burke and . Gemcitabine, Cancer Nurs, 1999.

W. Hagmann, R. Jesnomski, and J. M. Löhr, Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells, Neoplasia, 2010.

J. L. Spratlin and J. R. Mackey, Human Equilibrative Nucleoside Transporter 1 (hENT1) in Pancreatic Adenocarcinoma: Towards Individualized Treatment Decisions, Cancers, vol.2, issue.4, pp.2044-54, 2010.

J. García-manteiga, M. Molina-arcas, F. J. Casado, A. Mazo, and M. Pastor-anglada, Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2',2'-difluorodeoxycytidine-induced cytotoxicity, Clin Cancer Res Off J Am Assoc Cancer Res, vol.15, issue.13, pp.5000-5008, 2003.

D. S. Choi, M. Handa, H. Young, A. S. Gordon, I. Diamond et al., Genomic organization and expression of the mouse equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporter 1 (ENT1) gene, Biochem Biophys Res Commun, vol.277, issue.1, pp.200-208, 2000.

H. Ueno, K. Kiyosawa, and N. Kaniwa, Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?, British Journal of Cancer, 2007.

L. Bildstein, C. Dubernet, V. Marsaud, and H. Chacun, Transmembrane diffusion of gemcitabine by a nanoparticulate squalenoyl prodrug: an original drug delivery pathway, J Control Release, 2010.

M. Vandana and S. K. Sahoo, Long circulation and cytotoxicity of PEGylated gemcitabine and its potential for the treatment of pancreatic cancer, Biomaterials, vol.31, issue.35, pp.9340-56, 2010.

E. Moysan, G. Bastiat, and J. P. Benoit, Gemcitabine versus Modified Gemcitabine: a review of several promising chemical modifications, Mol Pharm, 2013.
URL : https://hal.archives-ouvertes.fr/inserm-00787112

E. Poplin, H. Wasan, R. L. Raponi, M. Ikdahl, T. Bondarenko et al., Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity, J Clin Oncol Off J Am Soc Clin Oncol, vol.31, issue.35, pp.4453-61, 2013.

M. Svrcek, J. Cros, R. Maréchal, J. Bachet, J. Fléjou et al., Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: a comparison between murine and rabbit antibodies, Histopathology, vol.66, issue.3, pp.457-62, 2015.

M. Hidalgo, S. Cascinu, J. Kleeff, R. Labianca, J. Löhr et al., Addressing the challenges of pancreatic cancer: Future directions for improving outcomes, Pancreatol Off J Int Assoc Pancreatol IAP Al, vol.15, issue.1, pp.8-18, 2015.

A. Grothey, D. Sargent, R. M. Goldberg, and H. Schmoll, Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment, J Clin Oncol Off J Am Soc Clin Oncol, vol.22, issue.7, pp.1209-1223, 2004.

T. Conroy, F. Desseigne, and Y. Marc, FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer, The New England Journal of Medicine, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00598658

M. E. Wall and M. C. Wani, Camptothecin and Taxol: Discovery to Clinic-Thirteenth Bruce F. Cain Memorial Award Lecture, Cancer Res, vol.55, issue.4, pp.753-60, 1995.

C. Belli, S. Cereda, and M. Reni, Role of taxanes in pancreatic cancer, World J Gastroenterol WJG, vol.18, issue.33, pp.4457-65, 2012.

A. Viúdez, N. Ramírez, I. Hernández-garcía, F. L. Carvalho, R. Vera et al., Nab-paclitaxel: A flattering facelift, Crit Rev Oncol Hematol, vol.92, issue.3, pp.166-80, 2014.

K. L. Hennenfent and R. Govindan, Novel formulations of taxanes: a review. Old wine in a new bottle? Ann Oncol, vol.17, pp.735-784, 2006.

D. A. Yardley, nab-Paclitaxel mechanisms of action and delivery, J Controlled Release, vol.170, issue.3, pp.365-72, 2013.

M. Al-hajeili, A. S. Azmi, and M. Choi, Nab-paclitaxel: potential for the treatment of advanced pancreatic cancer. OncoTargets Ther, vol.7, pp.187-92, 2014.

N. Desai, V. Trieu, and B. Damascelli, Soon-Shiong P. SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients, Transl Oncol, vol.2, issue.2, pp.59-64, 2009.

A. Neesse, K. K. Frese, D. S. Chan, T. E. Bapiro, W. J. Howat et al., SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice, Gut, vol.63, issue.6, pp.974-83, 2014.

K. K. Frese, A. Neesse, and N. Cook, nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov, 2012.

V. Hoff, D. D. Ervin, T. Arena, and F. P. , Increased Survival in Pancreatic Cancerwith nab-Paclitaxel plus Gemcitabine, The New England Journal of Medicine, 2013.

L. Hazard, The Role of Radiation Therapy in Pancreas Cancer, Gastrointest Cancer Res, 2009.

S. Jones, X. Zhang, D. W. Parsons, J. Lin, R. J. Leary et al., Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science, vol.321, issue.5897, pp.1801-1807, 2008.

M. W. Saif, Advanced stage pancreatic cancer: novel therapeutic options, Expert Rev Clin Pharmacol, vol.7, issue.4, pp.487-98, 2014.

M. Erkan, C. Reiser-erkan, C. W. Michalski, and J. Kleeff, Tumor microenvironment and progression of pancreatic cancer, Exp Oncol, vol.32, issue.3, pp.128-159, 2010.

M. V. Apte, J. S. Wilson, A. Lugea, and S. J. Pandol, A Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment, Gastroenterology, vol.144, issue.6, pp.1210-1219, 2013.

*. Bachem, . Mg, *. Schneider, *. Groß, ?. Weidenbach et al., Identification, culture, and characterization of pancreatic stellate cells in rats and humans, Gastroenterology, vol.115, issue.2, pp.421-453, 1998.

J. Mössner, Inflammatory Pancreatic Diseases. Karger Medical and Scientific Publishers, vol.68, 2005.

C. Duluc, S. Moatassim-billah, M. Chalabi-dchar, A. Perraud, R. Samain et al., Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance, EMBO Mol Med, 2015.
URL : https://hal.archives-ouvertes.fr/hal-02421448

A. C. Koong, V. K. Mehta, Q. T. Le, G. A. Fisher, D. J. Terris et al., Pancreatic tumors show high levels of hypoxia, Int J Radiat Oncol Biol Phys, vol.48, issue.4, pp.919-941, 2000.

M. Schneider, P. Büchler, N. Giese, T. Giese, J. Wilting et al., Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread, Int J Oncol, vol.28, issue.4, pp.883-90, 2006.

V. Secq, J. Leca, C. Bressy, F. Guillaumond, P. Skrobuk et al., Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling, Cell Death Dis, vol.6, issue.1, p.1592, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01234631

Z. Zhu, J. Kleeff, H. Kayed, L. Wang, M. Korc et al., Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells, Mol Carcinog, vol.35, issue.3, pp.138-185, 2002.

H. Funahashi, Y. Okada, H. Sawai, H. Takahashi, Y. Matsuo et al., The role of glial cell line-derived neurotrophic factor (GDNF) and integrins for invasion and metastasis in human pancreatic cancer cells, J Surg Oncol, vol.91, issue.1, pp.77-83, 2005.

F. H. Schmitz-winnenthal, C. Volk, Z. 'graggen, K. Galindo, L. Nummer et al., High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients, Cancer Res, vol.65, issue.21, pp.10079-87, 2005.

N. Hiraoka, K. Onozato, T. Kosuge, and S. Hirohashi, Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions, Clin Cancer Res Off J Am Assoc Cancer Res, vol.12, issue.18, pp.5423-5457, 2006.

V. Bernstorff, W. Voss, M. Freichel, S. Schmid, A. Vogel et al., Systemic and local immunosuppression in pancreatic cancer patients, Clin Cancer Res Off J Am Assoc Cancer Res, vol.7, issue.3, pp.925-932, 2001.

V. Bernstorff, W. Spanjaard, R. A. Chan, A. K. Lockhart, D. C. Sadanaga et al., Pancreatic cancer cells can evade immune surveillance via nonfunctional Fas (APO-1/CD95) receptors and aberrant expression of functional Fas ligand, Surgery, vol.125, issue.1, pp.73-84, 1999.

S. R. Bramhall, The matrix metalloproteinases and their inhibitors in pancreatic cancer. From molecular science to a clinical application, Int J Pancreatol Off J Int Assoc Pancreatol, vol.21, issue.1, pp.1-12, 1997.

H. Yamamoto, F. Itoh, S. Iku, Y. Adachi, H. Fukushima et al., Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression, J Clin Oncol Off J Am Soc Clin Oncol, vol.19, issue.4, pp.1118-1145, 2001.

S. Ohnami, N. Matsumoto, M. Nakano, K. Aoki, K. Nagasaki et al., Identification of genes showing differential expression in antisense K-ras-transduced pancreatic cancer cells with suppressed tumorigenicity, Cancer Res, vol.59, issue.21, pp.5565-71, 1999.

P. P. Provenzano and S. R. Hingorani, Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer, Br J Cancer, vol.108, issue.1, pp.1-8, 2013.

S. Lunardi, R. J. Muschel, and T. B. Brunner, The stromal compartments in pancreatic cancer: are there any therapeutic targets? Cancer Lett, vol.343, pp.147-55, 2014.

C. Feig, A. Gopinathan, A. Neesse, D. S. Chan, N. Cook et al., The pancreas cancer microenvironment, Clin Cancer Res Off J Am Assoc Cancer Res, vol.18, issue.16, pp.4266-76, 2012.

D. M. Owens and F. M. Watt, Contribution of stem cells and differentiated cells to epidermal tumours, Nat Rev Cancer, vol.3, issue.6, pp.444-51, 2003.

M. Murone, A. Rosenthal, and F. J. De-sauvage, Sonic hedgehog signaling by the Patched-Smoothened receptor complex, Curr Biol, vol.9, issue.2, pp.76-84, 1999.

M. P. Magliano, . Di, S. Sekine, A. Ermilov, J. Ferris et al., Hedgehog/Ras interactions regulate early stages of pancreatic cancer, Genes Dev, vol.20, issue.22, pp.3161-73, 2006.

K. Quint, S. Stintzing, B. Alinger, C. Hauser-kronberger, O. Dietze et al., The Expression Pattern of PDX-1, SHH, Patched and Gli-1 Is Associated with Pathological and Clinical Features in Human Pancreatic Cancer, Pancreatology, vol.9, issue.1, pp.116-142, 2009.

J. P. Morton and B. C. Lewis, Shh signaling and pancreatic cancer: implications for therapy? Cell Cycle Georget Tex, vol.6, pp.1553-1560, 2007.

H. Tian, C. A. Callahan, K. J. Dupree, W. C. Darbonne, C. P. Ahn et al., Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis, Proc Natl Acad Sci, vol.106, issue.11, pp.4254-4263, 2009.

M. Rajurkar, W. E. De-jesus-monge, D. R. Driscoll, V. A. Appleman, H. Huang et al., Gli Transcriptional Activity Is Essential for Kras-Induced Pancreatic Tumorigenesis and Regulates IKBKE/NF-\(\kappa\)B Activity in the Tumor Epithelium, 2012.

M. Rodova, J. Fu, D. N. Watkins, R. K. Srivastava, and S. Shankar, Sonic Hedgehog Signaling Inhibition Provides Opportunities for Targeted Therapy by Sulforaphane in Regulating Pancreatic Cancer Stem Cell Self-Renewal, PLoS ONE, vol.7, issue.9, 2012.

H. Onishi and M. Katano, Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer, World J Gastroenterol WJG, vol.20, issue.9, pp.2335-2377, 2014.

C. B. Westphalen and K. P. Olive, Genetically Engineered Mouse Models of Pancreatic Cancer, Cancer J Sudbury Mass, vol.18, issue.6, pp.502-512, 2012.

K. P. Olive, M. A. Jacobetz, C. J. Davidson, A. Gopinathan, D. Mcintyre et al., Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer. Science, vol.324, pp.1457-61, 2009.

E. J. Kim, V. Sahai, E. V. Abel, K. A. Griffith, J. K. Greenson et al., Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma, Clin Cancer Res, 2014.

J. , O. Dwyer, P. J. Ramanathan, R. K. Hoff, D. Maitra et al., A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA), J Clin Oncol, p.32, 2014.

B. N. Singh, J. Fu, R. K. Srivastava, and S. Shankar, Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms, PloS One, vol.6, issue.11, p.27306, 2011.

M. A. Jacobetz, D. S. Chan, A. Neesse, T. E. Bapiro, N. Cook et al., Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer, Gut, vol.62, issue.1, pp.112-132, 2013.

J. H. Houtgraaf, J. Versmissen, and W. J. Van-der-giessen, A concise review of DNA damage checkpoints and repair in mammalian cells, Cardiovasc Revascularization Med Mol Interv, vol.7, issue.3, pp.165-72, 2006.

D. Branzei and M. Foiani, Maintaining genome stability at the replication fork, Nat Rev Mol Cell Biol, vol.11, issue.3, pp.208-227, 2010.

T. A. Potapova, J. Zhu, and R. Li, Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos, Cancer Metastasis Rev, 2013.

J. Chen, D. P. Silver, D. Walpita, S. B. Cantor, A. F. Gazdar et al., Stable Interaction between the Products of the BRCA1 and BRCA2 Tumor Suppressor Genes in Mitotic and Meiotic Cells, Mol Cell, vol.2, issue.3, pp.317-345, 1998.

P. L. Welcsh, K. N. Owens, and M. C. King, Insights into the functions of BRCA1 and BRCA2, Trends Genet TIG, vol.16, issue.2, pp.69-74, 2000.

O. Vyas, K. Leung, L. Ledbetter, K. Kaley, T. Rodriguez et al., Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation, Anticancer Drugs, vol.26, issue.2, pp.224-230, 2015.

F. J. Couch, M. R. Johnson, K. G. Rabe, K. Brune, M. De-andrade et al., The prevalence of BRCA2 mutations in familial pancreatic cancer, Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol, vol.16, issue.2, pp.342-348, 2007.

H. Farmer, N. Mccabe, C. J. Lord, A. Tutt, D. A. Johnson et al., Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature, vol.434, issue.7035, pp.917-938, 2005.

X. Luo and W. L. Kraus, On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev, vol.26, pp.417-449, 2012.

S. Tangutoori, P. Baldwin, and S. Sridhar, PARP inhibitors: A new era of targeted therapy, Maturitas, 2015.

J. Murai, S. Huang, A. Renaud, Y. Zhang, J. J. Takeda et al., Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib, Mol Cancer Ther, vol.13, issue.2, pp.433-476, 2014.

D. A. Jacob, M. Bahra, J. M. Langrehr, S. Boas-knoop, R. Stefaniak et al., Combination therapy of poly (ADP-ribose) polymerase inhibitor 3-aminobenzamide and gemcitabine shows strong antitumor activity in pancreatic cancer cells, J Gastroenterol Hepatol, vol.22, issue.5, pp.738-786, 2007.

S. Chen, G. Wang, X. Niu, J. Zhao, W. Tan et al., Combination of AZD2281 (Olaparib) and GX15-070 (Obatoclax) results in synergistic antitumor activities in preclinical models of pancreatic cancer, Cancer Lett, vol.348, issue.1-2, pp.20-28, 2014.

J. Bendell, E. M. O'reilly, M. R. Middleton, I. Chau, H. Hochster et al., Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer, Ann Oncol Off J Eur Soc Med Oncol ESMO, vol.26, issue.4, pp.804-815, 2015.

J. Demoulin and A. Essaghir, PDGF receptor signaling networks in normal and cancer cells, Cytokine Growth Factor Rev, vol.25, issue.3, pp.273-83, 2014.

H. H. Sedlacek, Kinase inhibitors in cancer therapy: a look ahead, Drugs, vol.59, issue.3, pp.435-76, 2000.

R. A. Moss, D. Moore, M. F. Mulcahy, K. Nahum, B. Saraiya et al., A Multi-institutional Phase 2 Study of Imatinib Mesylate and Gemcitabine for First-Line Treatment of Advanced Pancreatic Cancer, Gastrointest Cancer Res GCR, vol.5, issue.3, pp.77-83, 2012.

A. Östman, PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev, vol.15, pp.275-86, 2004.

C. Gialeli, D. Nikitovic, D. Kletsas, A. D. Theocharis, G. N. Tzanakakis et al., PDGF/PDGFR signaling and targeting in cancer growth and progression: Focus on tumor microenvironment and cancer-associated fibroblasts, Curr Pharm Des, vol.20, issue.17, pp.2843-2851, 2014.

M. Fjällskog, M. H. Lejonklou, K. E. Oberg, B. K. Eriksson, and E. T. Janson, Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors, Clin Cancer Res Off J Am Assoc Cancer Res, vol.9, issue.4, pp.1469-73, 2003.

J. Taeger, C. Moser, C. Hellerbrand, M. E. Mycielska, G. Glockzin et al., Targeting FGFR/PDGFR/VEGFR Impairs Tumor Growth, Angiogenesis, and Metastasis by Effects on Tumor Cells, Endothelial Cells, and Pericytes in Pancreatic Cancer, Mol Cancer Ther, vol.10, issue.11, pp.2157-67, 2011.

A. Gonçalves, M. Gilabert, E. François, L. Dahan, H. Perrier et al., BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer, Ann Oncol Off J Eur Soc Med Oncol ESMO, vol.23, issue.11, pp.2799-805, 2012.

G. L. Beatty, E. G. Chiorean, M. P. Fishman, B. Saboury, U. R. Teitelbaum et al., CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans, Science, vol.331, issue.6024, pp.1612-1618, 2011.

G. L. Beatty, D. A. Torigian, E. G. Chiorean, B. Saboury, A. Brothers et al., A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma, Clin Cancer Res Off J Am Assoc Cancer Res, vol.19, issue.22, pp.6286-95, 2013.

R. M. Blaese, K. W. Culver, A. D. Miller, C. S. Carter, T. Fleisher et al., Lymphocyte-Directed Gene Therapy for ADA? SCID: Initial Trial Results After 4 Years, Science, vol.270, issue.5235, pp.475-80, 1995.

Y. Li, B. Li, C. Li, and L. Li, Key points of basic theories and clinical practice in rAd-p53 ( Gendicine TM ) gene therapy for solid malignant tumors, Expert Opin Biol Ther, vol.15, issue.3, pp.437-54, 2015.

S. P. Chawla, V. S. Chua, L. Fernandez, D. Quon, W. C. Blackwelder et al., Advanced Phase I/II Studies of Targeted Gene Delivery In Vivo: Intravenous Rexin-G for Gemcitabineresistant Metastatic Pancreatic Cancer, Mol Ther, vol.18, issue.2, pp.435-476, 2009.

B. Mishra and R. R. Patel, Gene Therapy for Treatment of Pancreatic Cancer, Austin Therapeutics, 2014.

T. Miseki, H. Kawakami, M. Natsuizaka, S. Darmanin, H. Y. Cui et al., Suppression of tumor growth by intra-muscular transfer of naked DNA encoding adrenomedullin antagonist. Cancer Gene Ther, vol.14, pp.39-44, 2007.

J. Xu, C. Jin, S. Hao, G. Luo, and D. Fu, Pancreatic cancer: gene therapy approaches and gene delivery systems, Expert Opin Biol Ther, vol.10, issue.1, pp.73-88, 2010.

Z. Khvalevsky, E. Gabai, R. Rachmut, I. H. Horwitz, E. Brunschwig et al., Mutant KRAS is a druggable target for pancreatic cancer, Proc Natl Acad Sci, vol.110, issue.51, pp.20723-20731, 2013.

N. Senzer, J. Nemunaitis, D. Nemunaitis, C. Bedell, G. Edelman et al., Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors, Mol Ther, vol.21, issue.5, pp.1096-103, 2013.

F. Vernejoul, L. Ghénassia, and A. Souque, Gene Therapy Based on Gemcitabine Chemosensitization Suppresses Pancreatic Tumor Growth, Molecular Therapy, 2006.

F. Vernejoul, P. Faure, N. Benali, D. Calise, G. Tiraby et al., Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models, Cancer Res, vol.62, issue.21, pp.6124-6155, 2002.

N. Carrere, F. Vernejoul, A. Souque, A. Asnacios, N. Vaysse et al., Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells, Hum Gene Ther, vol.16, issue.10, pp.1175-93, 2005.

F. Park, Lentiviral vectors: are they the future of animal transgenesis? Physiol Genomics, vol.31, pp.159-73, 2007.

S. Hacein-bey-abina, V. Kalle, C. Schmidt, M. Mccormack, M. P. Wulffraat et al., LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1, Science, vol.302, issue.5644, pp.415-424, 2003.

J. Young, Cellular Factors Involved in Early Steps of Retroviral Replication, vol.264, 2003.

E. Ravet, H. Lulka, F. Gross, L. Casteilla, L. Buscail et al., Using lentiviral vectors for efficient pancreatic, Cancer Gene Ther, vol.17, issue.5, pp.315-339, 2010.
URL : https://hal.archives-ouvertes.fr/inserm-00480870

T. Lucas, K. Benihoud, F. Vigant, C. Schmidt, M. G. Bachem et al., Hexon Modification to Improve the Activity of Oncolytic Adenovirus Vectors against Neoplastic and Stromal Cells in Pancreatic Cancer, PLoS ONE, vol.10, issue.2, p.117254, 2015.

R. Alba, A. Bosch, and M. Chillon, Gutless adenovirus: last-generation adenovirus for gene therapy, Gene Ther, vol.12, issue.1, pp.18-27, 2005.

G. W. Wolkersdörfer, C. Thiede, R. Fischer, G. Ehninger, and C. Haag, Adenoviral p53 gene transfer and gemcitabine in three patients with liver metastases due to advanced pancreatic carcinoma, HPB, vol.9, issue.1, pp.16-25, 2007.

L. K. Aguilar, L. A. Shirley, V. M. Chung, C. L. Marsh, J. Walker et al., Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma, Cancer Immunol Immunother CII, 2015.

J. M. Herman, A. T. Wild, H. Wang, P. T. Tran, K. J. Chang et al., Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results, J Clin Oncol Off J Am Soc Clin Oncol, vol.31, issue.7, pp.886-94, 2013.

U. Hieber and M. E. Heim, Tumor necrosis factor for the treatment of malignancies, Oncology, vol.51, issue.2, pp.142-53, 1994.

A. Chiocca and E. , Oncolytic viruses, Nat Rev Cancer, vol.2, issue.12, pp.938-50, 2002.
URL : https://hal.archives-ouvertes.fr/inserm-01644345

R. Maitra, R. Seetharam, L. Tesfa, T. A. Augustine, L. Klampfer et al., Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan, Oncotarget, vol.5, issue.9, pp.2807-2826, 2014.

. Oncolytics-biotech®-inc, Announces Overall and KRAS-Mutated Patient Data from U.S. Randomized Phase 2 Pancreatic Cancer Study, 2015.

G. N. Barber, Vesicular stomatitis virus as an oncolytic vector, Viral Immunol, vol.17, issue.4, pp.516-543, 2004.

A. M. Murphy, D. M. Besmer, M. Moerdyk-schauwecker, N. Moestl, D. A. Ornelles et al., Vesicular Stomatitis Virus as an Oncolytic Agent against Pancreatic Ductal Adenocarcinoma, J Virol, vol.86, issue.6, pp.3073-87, 2012.

B. D. Howard, L. Boenicke, B. Schniewind, D. Henne-bruns, and H. Kalthoff, Transduction of human pancreatic tumor cells with vesicular stomatitis virus G-pseudotyped retroviral vectors containing a herpes simplex virus thymidine kinase mutant gene enhances bystander effects and sensitivity to ganciclovir, Cancer Gene Ther, vol.7, issue.6, pp.927-965, 2000.

S. Bossow, C. Grossardt, A. Temme, M. Leber, S. Sawall et al., Armed and targeted measles virus for chemovirotherapy of pancreatic cancer, Cancer Gene Ther, vol.18, issue.8, pp.598-608, 2011.

H. Kasuya, S. Takeda, S. Nomoto, and A. Nakao, The potential of oncolytic virus therapy for pancreatic cancer, Cancer Gene Ther, vol.12, issue.9, pp.725-761, 2005.

C. Xu and H. L. , Viral Therapy for Pancreatic Cancer: Tackle the Bad Guys with Poison, Cancer Lett, 2013.

P. G. Spear, R. J. Eisenberg, and G. H. Cohen, Three classes of cell surface receptors for alphaherpesvirus entry, Virology, vol.275, issue.1, pp.1-8, 2000.

G. Zhou, G. Ye, W. Debinski, and B. Roizman, Engineered herpes simplex virus 1 is dependent on IL13Ralpha 2 receptor for cell entry and independent of glycoprotein D receptor interaction, Proc Natl Acad Sci, vol.99, issue.23, pp.15124-15133, 2002.

L. Menotti, G. Nicoletti, V. Gatta, S. Croci, L. Landuzzi et al., Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells, Proc Natl Acad Sci, vol.106, issue.22, pp.9039-9083, 2009.

R. J. Eisenberg, D. Atanasiu, T. M. Cairns, J. R. Gallagher, C. Krummenacher et al., Herpes Virus Fusion and Entry: A Story with Many Characters, Viruses, vol.4, issue.5, pp.800-832, 2012.

M. G. Schlieman, B. N. Fahy, R. Ramsamooj, L. Beckett, and R. J. Bold, Incidence, mechanism and prognostic value of activated AKT in pancreas cancer, Br J Cancer, vol.89, issue.11, pp.2110-2115, 2003.

F. Sarinella, A. Calistri, P. Sette, G. Palù, and C. Parolin, Oncolysis of pancreatic tumour cells by a gamma34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway. Gene therapy, 2006.

R. L. Martuza, A. Malick, J. M. Markert, K. L. Ruffner, and D. M. Coen, Experimental therapy of human glioma by means of a genetically engineered virus mutant, Science, 1991.

C. M. Kramm, M. Chase, U. Herrlinger, A. Jacobs, P. A. Pechan et al., Therapeutic efficiency and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy. Hum Gene Ther, vol.8, pp.2057-68, 1997.

R. Y. Chung, Y. Saeki, and E. A. Chiocca, B-myb Promoter Retargeting of Herpes Simplex Virus ?34.5 Gene-Mediated Virulence toward Tumor and Cycling Cells, J Virol, vol.73, issue.9, pp.7556-64, 1999.

R. Y. Chung, Y. Saeki, and E. A. Chiocca, B-myb promoter retargeting of herpes simplex virus gamma34.5 gene-mediated virulence toward tumor and cycling cells, J Virol, vol.73, issue.9, pp.7556-64, 1999.

M. J. Parr, Y. Manome, T. Tanaka, P. Wen, D. W. Kufe et al., Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector, Nat Med, vol.3, issue.10, pp.1145-1154, 1997.

J. M. Markert, M. D. Medlock, S. D. Rabkin, G. Y. Gillespie, T. Todo et al., Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial, Gene Ther, vol.7, issue.10, pp.867-74, 2000.

A. Nakao, H. Kasuya, T. T. Sahin, N. Nomura, A. Kanzaki et al., A phase I doseescalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer, Cancer Gene Ther, vol.18, issue.3, pp.167-75, 2011.

H. L. Kaufman and S. D. Bines, OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma, Future Oncol, vol.6, issue.6, pp.941-950, 2010.

J. R. Bischoff, D. H. Kirn, A. Williams, C. Heise, S. Horn et al., An Adenovirus Mutant That Replicates Selectively in p53-Deficient Human Tumor Cells, Science, vol.274, issue.5286, pp.373-379, 1996.

J. R. Hecht, R. Bedford, J. L. Abbruzzese, S. Lahoti, T. R. Reid et al., A Phase I/II Trial of Intratumoral Endoscopic Ultrasound Injection of ONYX-015 with Intravenous Gemcitabine in Unresectable Pancreatic Carcinoma, Clin Cancer Res, vol.9, issue.2, pp.555-61, 2003.

G. Chen, S. Zhang, X. He, S. Liu, C. Ma et al., Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives, OncoTargets Ther, vol.7, pp.1901-1910, 2014.

A. Rodríguez-garcía, M. Giménez-alejandre, J. J. Rojas, R. Moreno, M. Bazan-peregrino et al., Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression, Clin Cancer Res, 2014.

S. O. Freytag, K. N. Barton, S. L. Brown, V. Narra, Y. Zhang et al., Replication-competent adenovirus-mediated suicide gene therapy with radiation in a preclinical model of pancreatic cancer, Mol Ther J Am Soc Gene Ther, vol.15, issue.9, pp.1600-1606, 2007.

A. E. Tollefson, A. Scaria, T. W. Hermiston, J. S. Ryerse, L. J. Wold et al., The adenovirus death protein (E3-11.6K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells, J Virol, vol.70, issue.4, pp.2296-306, 1996.

L. Buscail, B. Bournet, F. Vernejoul, G. Cambois, H. Lulka et al., First-in-man phase I clinical trial of gene therapy for advanced pancreatic cancer: Safety, biodistribution and preliminary clinical findings, Mol Ther J Am Soc Gene Ther, 2015.

E. S. Arner and S. Eriksson, Mammalian deoxyribonucleoside kinases, Pharmacol Ther, 1995.

V. W. Van-haperen, G. Veerman, J. B. Vermorken, H. M. Pinedo, and G. Peters, Regulation of phosphorylation of deoxycytidine and 2',2'-difluorodeoxycytidine (gemcitabine); effects of cytidine 5'-triphosphate and uridine 5'-triphosphate in relation to chemosensitivity for 2',2'-difluorodeoxycytidine, Biochem Pharmacol, 1996.

J. R. Kroep, W. J. Loves, L. Clasina, and . Van-der-wilt, Pretreatment Deoxycytidine Kinase Levels Predict in Vivo Gemcitabine Sensitivity. Molecular Cancer Therapeutics, 2002.

S. Ohhashi, K. Ohuchida, and K. Mizumoto, Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer, Anticancer Res, 2008.

R. Maréchal, J. Bachet, J. R. Mackey, C. Dalban, P. Demetter et al., Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma, Gastroenterology, vol.143, issue.3, pp.1-6, 2012.

C. L. Costantino, A. K. Witkiewicz, Y. Kuwano, and J. A. Cozzitorto, The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Research, 2009.

D. M. Hapke, A. P. Stegmann, and B. S. Mitchell, Retroviral transfer of deoxycytidine kinase into tumor cell lines enhances nucleoside toxicity, Cancer Res, 1996.

P. Rochaix, N. Delesque, J. P. Estève, N. Saint-laurent, J. J. Voight et al., Gene therapy for pancreatic carcinoma: local and distant antitumor effects after somatostatin receptor sst2 gene transfer. Hum Gene Ther, vol.10, pp.995-1008, 1999.

M. Chalabi-dchar, S. Cassant-sourdy, C. Duluc, M. Fanjul, H. Lulka et al., Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16, Gastroenterology, 2015.
URL : https://hal.archives-ouvertes.fr/inserm-02472216

F. Barbieri, A. Bajetto, A. Pattarozzi, M. Gatti, . W&#xfc et al., Peptide Receptor Targeting in Cancer: The Somatostatin Paradigm, Int J Pept, p.926295, 2013.

L. Buscail, N. Saint-laurent, E. Chastre, J. Vaillant, C. Gespach et al., Loss of sst2 Somatostatin Receptor Gene Expression in Human Pancreatic and Colorectal Cancer, Cancer Res, vol.56, issue.8, pp.1823-1830, 1996.

N. Delesque, L. Buscail, J. Estève, N. Saint-laurent, C. Müller et al., sst2 Somatostatin Receptor Expression Reverses Tumorigenicity of Human Pancreatic Cancer Cells, Cancer Res, vol.57, issue.5, pp.956-62, 1997.

N. Benali, P. Cordelier, D. Calise, P. Pages, P. Rochaix et al., Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238, Proc Natl Acad Sci, vol.97, issue.16, pp.9180-9185, 2000.

N. Hanna, P. Ohana, F. M. Konikoff, G. Leichtmann, A. Hubert et al., Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer, Cancer Gene Ther, vol.19, issue.6, pp.374-81, 2012.

P. Wang, L. Zhuang, J. Zhang, J. Fan, J. Luo et al., The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL, Mol Oncol, vol.7, issue.3, pp.334-379, 2013.

J. J. Farrell, H. Elsaleh, M. Garcia, and R. Lai, Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer, Gastroenterology, 2009.

P. Casanello, A. Torres, F. Sanhueza, M. González, M. Farías et al., Equilibrative nucleoside transporter 1 expression is downregulated by hypoxia in human umbilical vein endothelium, Circ Res, vol.97, issue.1, pp.16-24, 2005.

Y. G. Goan, B. Zhou, E. Hu, M. S. Yen, and Y. , Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line, Cancer Res, 1999.

A. M. Bergman, P. P. Eijk, V. Ruiz-van-haperen, K. Smid, G. Veerman et al., In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant, Cancer Res, vol.65, issue.20, pp.9510-9516, 2005.

E. Giovannetti, N. Funel, G. J. Peters, D. Chiaro, and M. , MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity, Cancer Res, 2010.

X. Pan, Z. X. Wang, and R. Wang, MicroRNA-21: a novel therapeutic target in human cancer, Cancer Biol Ther, 2010.

S. Fujita, T. Ito, T. Mizutani, S. Minoguchi, N. Yamamichi et al., miR-21 Gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism, J Mol Biol, vol.378, issue.3, pp.492-504, 2008.

J. Niu, Y. Shi, and G. Tan, DNA damage induces NF-?B-dependent microRNA-21 up-regulation and promotes breast cancer cell invasion, J Biol Chem, 2012.

J. Du, S. Yang, D. An, F. Hu, W. Yuan et al., BMP-6 inhibits microRNA-21 expression in breast cancer through repressing deltaEF1 and AP-1, Cell Res, vol.19, issue.4, pp.487-96, 2009.

X. Liu, J. Feng, L. Tang, L. Liao, Q. Xu et al., The regulation and function of miR-21-FOXO3a-miR-34b/c signaling in breast cancer, Int J Mol Sci, vol.16, issue.2, pp.3148-62, 2015.

F. Sicard, M. Gayral, H. Lulka, L. Buscail, and P. Cordelier, Targeting miR-21 for the Therapy of Pancreatic Cancer, Molecular Therapy, 2013.

R. D. , Biology of Giardia lamblia, CLINICAL MICROBIOLOGY REVIEWS, 2001.

R. Andersson, U. Aho, B. I. Nilsson, G. J. Peters, M. Pastor-anglada et al., Gemcitabine chemoresistance in pancreatic cancer: Molecular mechanisms and potential solutions, Scand J Gastroenterol, vol.44, issue.7, pp.782-788, 2009.

E. Chung, H. Yamashita, P. Au, B. A. Tannous, D. Fukumura et al., Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases, PloS One, vol.4, issue.12, p.8316, 2009.

M. Schleicher, B. R. Shepherd, Y. Suarez, C. Fernandez-hernando, Y. J. Pan et al., Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence, J Cell Biol, vol.180, issue.1, pp.101-113, 2008.

C. Osman, C. Merkwirth, and T. Langer, Prohibitins and the functional compartmentalization of mitochondrial membranes, J Cell Sci, vol.122, pp.3823-3853, 2009.

H. E. Deubzer, M. C. Schier, I. Oehme, M. Lodrini, B. Haendler et al., HDAC11 is a novel drug target in carcinomas, Int J Cancer J Int Cancer, vol.132, issue.9, pp.2200-2208, 2013.

X. Zhu, N. Liu, W. Liu, S. Song, and K. Guo, Silencing of the integrin-linked kinase gene suppresses the proliferation, migration and invasion of pancreatic cancer cells (Panc-1), Genet Mol Biol, vol.35, issue.2, pp.538-582, 2012.

M. S. Duxbury, H. Ito, E. Benoit, T. Waseem, S. W. Ashley et al., RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance, Clin Cancer Res Off J Am Assoc Cancer Res, vol.11, issue.9, pp.3433-3441, 2005.

A. Aze, J. C. Zhou, A. Costa, and V. Costanzo, DNA replication and homologous recombination factors: acting together to maintain genome stability, Chromosoma, vol.122, issue.5, pp.401-414, 2013.

S. S. Müerköster, V. Werbing, D. Koch, B. Sipos, O. Ammerpohl et al., Role of myofibroblasts in innate chemoresistance of pancreatic carcinoma--epigenetic downregulation of caspases, Int J Cancer J Int Cancer, vol.123, issue.8, pp.1751-60, 2008.

F. Cividini, D. N. Filoni, R. Pesi, S. Allegrini, M. Camici et al., IMP-GMP specific cytosolic 5'-nucleotidase regulates nucleotide pool and prodrug metabolism, Biochim Biophys Acta, vol.1850, issue.7, pp.1354-61, 2015.

T. Arumugam, V. Ramachandran, K. F. Fournier, H. Wang, L. Marquis et al., Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer, Cancer Res, vol.69, issue.14, pp.5820-5828, 2009.

N. Funamizu, A. Okamoto, Y. Kamata, T. Misawa, T. Uwagawa et al., Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase? Oncol Rep, vol.23, pp.471-476, 2010.

G. M. Cooper and S. Greer, The Effect of Inhibition of Cytidine Deaminase by Tetrahydrouridine on the Utilization of Deoxycytidine and 5-Bromodeoxycytidine for Deoxyribonucleic Acid Synthesis, Mol Pharmacol, vol.9, issue.6, pp.698-703, 1973.

M. Leader, M. Collins, J. Patel, and K. Henry, Vimentin: an evaluation of its role as a tumour marker, Histopathology, vol.11, issue.1, pp.63-72, 1987.

Y. Naito and C. A. Iacobuzio-donahue, Biomarker Profiles Associated with Metastatic Pancreatic Cancer, Mod Pathol, vol.23, pp.366-366, 2010.

M. M. Javle, J. F. Gibbs, K. K. Iwata, Y. Pak, P. Rutledge et al., Epithelial-Mesenchymal Transition (EMT) and Activated Extracellular Signal-regulated Kinase (p-Erk) in Surgically Resected Pancreatic Cancer, Ann Surg Oncol, vol.14, issue.12, pp.3527-3560, 2007.

S. Dimauro and E. A. Schon, Mitochondrial Respiratory-Chain Diseases, N Engl J Med, vol.348, issue.26, pp.2656-68, 2003.
URL : https://hal.archives-ouvertes.fr/hal-00537248

S. Dröse and U. Brandt, Molecular mechanisms of superoxide production by the mitochondrial respiratory chain, Adv Exp Med Biol, vol.748, pp.145-69, 2012.

H. Nakamura, H. Kasuya, J. T. Mullen, S. S. Yoon, T. M. Pawlik et al., Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5, J Clin Invest, vol.109, issue.7, pp.871-82, 2002.

B. J. Passer, T. Cheema, B. Zhou, H. Wakimoto, C. Zaupa et al., Identification of the ENT1 Antagonists Dipyridamole and Dilazep as Amplifiers of Oncolytic Herpes Simplex Virus-1

, Cancer Res, vol.70, issue.10, pp.3890-3895, 2010.

C. J. Larocca, J. Han, T. Gavrikova, L. Armstrong, A. R. Oliveira et al., Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer, 2015.

A. F. Hezel, A. C. Kimmelman, B. Z. Stanger, N. Bardeesy, and R. A. Depinho, Genetics and biology of pancreatic ductal adenocarcinoma, Genes Dev, vol.20, issue.10, pp.1218-1267, 2006.

F. Ye, C. Song, Z. Cao, C. Xia, D. Chen et al., Cytidine deaminase axis modulated by miR-484 differentially regulates cell proliferation and chemoresistance in breast cancer, Cancer Res, 2014.

E. Cros, L. Jordheim, C. Dumontet, and C. M. Galmarini, Problems Related to Resistance to Cytarabine in Acute Myeloid Leukemia. Leuk Lymphoma, vol.45, pp.1123-1155, 2004.

N. Weizman, Y. Krelin, M. Amit, and Z. Gil, Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase, Oncogene, 2013.

M. Amit and Z. Gil, Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase. OncoImmunology, 2013.

Q. Ebrahem, R. Z. Mahfouz, K. P. Ng, and Y. Saunthararajah, High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects, Oncotarget, 2012.

R. G. Stoller, C. E. Myers, and B. A. Chabner, Analysis of cytidine deaminase and tetrahydrouridine interaction by use of ligand techniques, Biochem Pharmacol, 1978.

E. M. Newman, R. J. Morgan, S. Kummar, J. H. Beumer, M. S. Blanchard et al., A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine, Cancer Chemother Pharmacol, vol.75, issue.3, pp.537-583, 2015.

F. Huq, Molecular modeling analysis of the metabolism of zebularine, Journal of pharmacology and toxicology, 2006.

C. B. Yoo, J. C. Chuang, H. Byun, G. Egger, A. S. Yang et al., Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice, Cancer Prev Res, vol.1, issue.4, pp.233-273, 2008.

M. Löffler, J. Jöckel, G. Schuster, and C. Becker, Dihydroorotat-ubiquinone oxidoreductase links mitochondria in the biosynthesis of pyrimidine nucleotides, Mol Cell Biochem, vol.174, issue.1-2, pp.125-134, 1997.

C. S. Ahn and C. M. Metallo, Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab, vol.3, p.1, 2015.

J. Fang, T. Uchiumi, M. Yagi, S. Matsumoto, R. Amamoto et al., Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction, Biosci Rep, vol.33, issue.2, p.21, 2013.

A. A. Khutornenko, A. A. Dalina, B. V. Chernyak, P. M. Chumakov, and A. G. Evstafieva, The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III. Acta Naturae, vol.6, pp.69-75, 2014.

J. Krungkrai, Malarial dihydroorotate dehydrogenase mediates superoxide radical production, Biochem Int, vol.24, issue.5, pp.833-842, 1991.

G. P. Dunn, A. T. Bruce, H. Ikeda, L. J. Old, and R. D. Schreiber, Cancer immunoediting: from immunosurveillance to tumor escape, Nat Immunol, vol.3, issue.11, pp.991-999, 2002.

D. T. Le, A. Wang-gillam, V. Picozzi, T. F. Greten, T. Crocenzi et al., Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes-Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer, J Clin Oncol Off J Am Soc Clin Oncol, vol.33, issue.12, pp.1325-1358, 2015.

C. A. Petrulio and H. L. Kaufman, Development of the PANVAC-VF vaccine for pancreatic cancer, Expert Rev Vaccines, vol.5, issue.1, pp.9-19, 2006.

H. L. Kaufman, S. Kim-schulze, K. Manson, G. Deraffele, J. Mitcham et al., Poxvirusbased vaccine therapy for patients with advanced pancreatic cancer, J Transl Med, vol.5, p.60, 2007.

M. K. Brenner, S. Gottschalk, A. M. Leen, and J. F. Vera, Is cancer gene therapy an empty suit? Lancet Oncol, vol.14, pp.447-56, 2013.

G. L. Beatty, A. R. Haas, M. V. Maus, D. A. Torigian, M. C. Soulen et al., Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies, Cancer Immunol Res, 2013.

C. Lü, A. K. Williams, V. Chalasani, C. H. Martínez, and J. Chin, Immunotherapy for metastatic prostate cancer: where are we at with sipuleucel-T? Expert Opin Biol Ther, vol.11, pp.99-108, 2011.

T. Ohta, H. Hori, M. Ogawa, M. Miyahara, H. Kawasaki et al., Impact of cytidine deaminase activity on intrinsic resistance to cytarabine in carcinoma cells, Oncol Rep, vol.12, issue.5, pp.1115-1135, 2004.

J. K. Schröder, C. Kirch, S. Seeber, and J. Schütte, Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia, Br J Haematol, vol.103, issue.4, pp.1096-103, 1998.

X. Liu, W. Wang, L. Lin, and S. Song, Expression of Gemcitabine-resistance-related gene and polymorphism of ribonucleotide reductase M1 gene promoter in Gemcitabine-resistant A549/Gem and NCI-H460/Gem cell lines

, Zhonghua Zhong Liu Za Zhi, vol.32, issue.1, pp.17-21, 2010.

R. Siegel, D. Naishadham, and A. Jemal, Cancer statistics, CA Cancer J Clin, vol.63, pp.11-30, 2013.

E. Costello, W. Greenhalf, and J. P. Neoptolemos, New biomark ers and targets in pancreatic cancer and their application to treatment, Nat Rev Gastroenterol Hepatol, vol.9, pp.435-444, 2012.

S. Jones, X. Zhang, D. W. Parsons, J. C. Lin, R. J. Leary et al., Core signaling pathways in human pan creatic cancers revealed by global genomic analyses, Science, vol.321, pp.1801-1806, 2008.

S. Yachida, S. Jones, I. Bozic, T. Antal, R. Leary et al., Distant metastasis occurs late during the genetic evolution of pancreatic cancer, Nature, vol.467, pp.1114-1117, 2010.

P. J. Campbell, S. Yachida, L. J. Mudie, P. J. Stephens, E. D. Pleasance et al., The patterns and dynamics of genomic in stability in metastatic pancreatic cancer, Nature, vol.467, pp.1109-1113, 2010.

S. Volinia, G. A. Calin, C. G. Liu, S. Ambs, A. Cimmino et al., A microRNA expression signature of human solid tumors defines cancer gene targets, Proc Nat! Acad Sei, vol.103, pp.2257-2261, 2006.

D. P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and fonction, Cel!, vol.116, pp.281-297, 2004.

V. N. Kim, J. Han, and M. C. Siomi, Biogenesis of small RNAs in ani mals, Nat Rev Mol Cel! Biol, vol.10, pp.126-139, 2009.

R. S. Redis, I. Berindan-neagoe, V. I. Pop, and G. A. Calin, Non-coding RNAs as theranostics in human cancers, J Cel! Biochern, 2012.

, , vol.113, pp.1451-1459

M. V. Iorio and C. M. Croce, MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review, EMBO Mol Med, vol.4, pp.143-159, 2012.

M. V. Iorio and C. M. Croce, microRNA involvement in human cancer, Carcinogenesis, vol.33, pp.1126-1133, 2012.

M. V. Iorio and C. M. Croce, Causes and consequences of mi croRNA dysregulation, Cancer J, vol.18, pp.215-222, 2012.

G. J. Tsongalis, G. Calin, P. Cordelier, C. Croce, F. Monzon et al., MicroRNA analysis: is it ready for prime time?, Clin Chem, vol.59, pp.343-347, 2013.

D. Leva, G. Croce, and C. M. , miRNA profiling of cancer, Curr Opin Genet Dev, vol.23, pp.3-11, 2013.

M. Gayral, MicroRNAs in pancreatic cancer

A. E. Frampton, T. M. Gall, L. Castellano, J. Stebbing, L. R. Jiao et al., Towards a clinical use of miRNAs in paru:reati.c can-30 cer biopsies, Expert Rev Mol Dillgn, vol.13, pp.31-34, 2013.

C. Wan, Y. Shen, T. Yang, T. Wang, L. Chen et al., Diagnostic value of microRNA for pancreati.c cancer: a meta.-analysi.s, Arch Merl Sei, vol.8, pp.749-755, 2012.

M. Gayral, J. Tonisani, and P. Cordelier, Current Understanding of microRNAs as Therapeutic Targets in Cancer, Toxicology and Medicine, pp.167-172, 2013.

M. Humeau, J. Tonisani, and P. Cordelier, miRNA in clinical practi.ce: paru:reatic cancer, Qin Biochem, vol.46, pp.933-936, 2013.

Y. Delpu, N. Hanoun, H. Lulka, F. Sicard, J. Selves et al., Genetie and epigenetic alterations in pancreatic carcinogenesis, Curr Genomics, vol.12, pp.15-24, 2011.

E. J. Lee, Y. Gusev, J. Jiang, G. J. Nuovo, M. R. Lerner et al., Expression profiling identifies microRNA signature in pancreatic cancer, Int J Cllncer, vol.120, pp.1046-1054, 2007.

J. K. Park, J. C. Henry, J. Jiang, C. Esau, Y. Gusev et al., , p.34

R. G. Postier, D. J. Brackett, and T. D. Schmittgen, miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor, Biochem Biophys Res Commun, vol.406, pp.518-523, 2011.

S. Zhang, J. Hao, F. Xie, X. Hu, C. Liu et al., , p.35

C. Shao, Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development, Cllrc:inogenesis, vol.32, pp.1183-1189, 2011.

S. Yu, Z. Lu, C. Liu, Y. Meng, Y. Ma et al., Chen 36 J. miRNA-% suppresses KR.AS and functions as a tumor suppressor gene in pancreatic cancer, Cllncer Res, vol.70, pp.6015-6025, 2010.

Q. Ji, X. Hao, M. Zhang, M. Li, L. Xiang et al., , p.37

, MicroRNA miR-34 inhibits hum.an pancreatic cancer tumorinitiating cells, PLoS One, vol.4, p.6816, 2009.

M. Dillhoff, J. Liu, W. Frankel, C. Croce, and M. Bloomston, Mi-croRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival, J Gastrointest Surg, vol.12, pp.2171-2176, 2008.

M. Bloomston, W. L. Frankel, F. Petrocca, S. Volinia, H. Alder et al., MicroR-NA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatiti.s. ]A, MA, vol.297, pp.1901-1908, 2007.

A. E. Szafranska, T. S. Davison, J. John, T. Cannon, B. Sipos et al., MicroRNA expression alterations are linked to tumorigenesi.s and non-neoplastic processes in pancreatic ductal adenocarcinoma, Oncogene, vol.26, pp.4442-4452, 2007.

N. Iloenaga, K. Ohuchida, K. Mizumoto, J. Yu, T. Kayashima et al., MicroRNA-203 expression as a new prognostic marker of paru:reatic adenocarcinoma, Ann Surg Oncol, vol.17, pp.3120-3128, 2010.

N. A. Schultz, J. Werner, H. Willenbrock, A. Roslind, N. Giese et al., MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma, Mad Plltlwl, vol.25, pp.1609-1622, 2012.

§. .. ,

. Wjg-i-www, , vol.170, p.11206

A. L. Collins, S. Wojcik, J. Liu, W. L. Frankel, H. Alder et al., A differential microRNA profile distinguishes cholangiocarcinoma from paru:reati.c adenocarcinoma, Ann Surg Oncol, vol.2, issue.1, pp.133-138, 2014.

A. E. Szafranska, M. Doleshal, H. S. Edmunds, G. 5. Luttges, J. Munding et al., let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression, Expert Roe Mal Diagn, vol.54, pp.831-844, 2008.

N. Hanoun, Y. Delpu, A. A. Suriawinata, B. Bournet, C. Bureau et al., The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis, Clin Chem, vol.56, pp.1107-1118, 2010.
URL : https://hal.archives-ouvertes.fr/inserm-00504774

T. Greither, L. F. Grochola, A. Udelnow, C. Lautenschuiger, P. Wurl et al., Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival, Int J Cancer, vol.126, pp.73-80, 2010.

J. Yu, K. Ohuchida, K. Mizumoto, N. Sato, T. Kayashima et al., hsa-miR-200c, is an independent pro gn osti.c factor in paru:reatic canoer and its upregulati.on inhibits pancreatic cancer invasion but increases cell proliferation, Mol Cancer, vol.9, p.169, 2010.

N. B. Jamieson, D. C. Morran, J. P. Morton, A. Ali, E. J. Dickson et al., Mi-croRNA molecular profiles associated with dia gn osis, clinicopathologic criteria, and overall survival in patients with resectable paru:reatic ductal adenocarcinoma, Qin Cancer Res, vol.18, pp.534-545, 2012.

N. A. Schultz, K. K. Andersen, A. Roslind, H. Willenbrock, M. W0jdemann et al., Prognostic microRNAs in cancer tissue from patients operated for pancreatic cancerfive microRNAs in a prognosti.c index, World J Surg, vol.36, pp.2699-2707, 2012.

G. Zhao, J. G. Zhang, Y. Shi, Q. Qin, Y. Liu et al., MiR-130b is a pro gn ostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3, PLoS One, vol.8, p.11, 2013.

V. Sudo, H. Falcone, A. Campani, D. Boggi, U. Peters et al., Highthroughput microRNA (miRNAs} arrays unravel the prognostic role of MiR-211 in pancreatic cancer, PZ.OS One, vol.7, p.49145, 2012.

H. A. Burris, M. J. Moore, J. Andersen, M. R. Green, M. L. Rothenberg et al., Von Hoff DD. lmprovements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced

A. Jemal, F. Bray, . Center, . Mm, J. Ferlay et al., Global cancer statistics, CA Cancer J Clin, vol.61, pp.69-90, 2011.

J. Torrisani, B. Bournet, . Cordelier, and L. Buscail, , 2008.

, Bull Cancer, vol.95, pp.503-512

T. Conroy, F. Desseigne, M. Ychou, O. Bouché, R. Guimbaud et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N Engl J Med, vol.364, pp.1817-1825, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00598658

Y. Delpu, N. Hanoun, H. Lulka, F. Sicard, J. Selves et al., Genetic and epigenetic alterations in pancreatic carcinogenesis, Curr Genomics, vol.12, pp.15-24, 2011.

. Iorio and C. M. Croce, MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review, EMBO Mol Med, vol.4, pp.143-159, 2012.

. Du-rieu, . Mc, J. Torrisani, J. Selves, A. Saati et al., , 2010.

, MicroRNA-21 is induced early in pancreatic ductal adenocarcinoma precursor lesions, Clin Chem, vol.56, pp.603-612

V. S. Nair, . Maeda, and J. P. Ioannidis, Clinical outcome prediction by microRNAs in human cancer: a systematic review, J Natl Cancer Inst, vol.104, pp.528-540, 2012.

X. Pan, . Wang, and R. Wang, MicroRNA-21: a novel therapeutic target in human cancer, Cancer Biol Ther, vol.10, pp.1224-1232, 2010.

I. Dufau, C. Frongia, F. Sicard, L. Dedieu, P. Cordelier et al., Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer, BMC Cancer, vol.12, p.15, 2012.
URL : https://hal.archives-ouvertes.fr/inserm-00670715

E. Chung, H. Yamashita, P. Au, . Tannous, . Ba et al., Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases, PLoS ONE, vol.4, p.8316, 2009.

C. Sabatel, L. Malvaux, N. Bovy, C. Deroanne, V. Lambert et al., MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells, PLoS ONE, vol.6, p.16979, 2011.

. Wang, . Olson, and . En, AngiomiRs-key regulators of angiogenesis, Curr Opin Genet Dev, vol.19, pp.205-211, 2009.

E. Costello and N. Greenhalf, New biomarkers and targets in pancreatic cancer and their application to treatment, Nat Rev Gastroenterol Hepatol, vol.9, pp.435-444, 2012.

S. Jones, X. Zhang, . Parsons, . Dw, J. C. Lin et al., Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science, vol.321, pp.1801-1806, 2008.

S. Yachida, S. Jones, . Bozic, R. Leary, and B. Fu, Distant metastasis occurs late during the genetic evolution of pancreatic cancer, Nature, vol.467, pp.1114-1117, 2010.

, www.moleculartherapy.org, vol.21, issue.5, 2013.

P. J. Campbell, S. Yachida, . Mudie, . Lj, . Stephens et al., The patterns and dynamics of genomic instability in metastatic pancreatic cancer, Nature, vol.467, pp.1109-1113, 2010.

T. Moriyama, K. Ohuchida, K. Mizumoto, J. Yu, N. Sato et al., MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance, Mol Cancer Ther, vol.8, pp.1067-1074, 2009.

E. Ravet, H. Lulka, F. Gross, L. Casteilla, . Buscail et al., Using lentiviral vectors for efficient pancreatic cancer gene therapy, Cancer Gene Ther, vol.17, pp.315-324, 2010.
URL : https://hal.archives-ouvertes.fr/inserm-00480870

N. Carrere, F. Vernejoul, A. Souque, A. Asnacios, N. Vaysse et al., Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells, Hum Gene Ther, vol.16, pp.1175-1193, 2005.

P. Cordelier, C. Bienvenu, H. Lulka, F. Marrache, M. Bouisson et al., Replication-deficient rSV40 mediate pancreatic gene transfer and long-term inhibition of tumor growth, Cancer Gene Ther, vol.14, pp.19-29, 2007.

B. Gentner, G. Schira, A. Giustacchini, M. Amendola, . Brown et al., Stable knockdown of microRNA in vivo by lentiviral vectors, Nat Methods, vol.6, pp.63-66, 2009.

. Durand and A. Cimarelli, The inside out of lentiviral vectors, Viruses, vol.3, pp.132-159, 2011.
URL : https://hal.archives-ouvertes.fr/hal-02322800

A. Moiani, Y. Paleari, D. Sartori, R. Mezzadra, A. Miccio et al., Lentiviral vector integration in the human genome induces alternative splicing and generates aberrant transcripts, J Clin Invest, vol.122, pp.1653-1666, 2012.

L. Shi, J. Chen, J. Yang, T. Pan, . Zhang et al., MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity, Brain Res, vol.1352, pp.255-264, 2010.

M. L. Si, S. Zhu, H. Wu, Z. Lu, . Wu et al., miR-21-mediated tumor growth, Oncogene, vol.26, pp.2799-2803, 2007.

J. K. Park, . Lee, E. Ej, . Schmittgen, and . Td, Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma, Pancreas, vol.38, pp.190-199, 2009.