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Pancreatic Neoplasms: HELP
Articles by Laurent Bartholin
Based on 9 articles published since 2010
(Why 9 articles?)

Between 2010 and 2020, L. Bartholin wrote the following 9 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Review Prognostic stratification of resected pancreatic ductal adenocarcinoma: Past, present, and future. 2018

Barhli, Aline / Cros, Jérôme / Bartholin, Laurent / Neuzillet, Cindy. ·INSERM UMR1149, Bichat-Beaujon University Hospital, AP-HP - PRES Paris 7 Diderot, Paris, France. · INSERM UMR1149, Bichat-Beaujon University Hospital, AP-HP - PRES Paris 7 Diderot, Paris, France; Department of Pathology, Bichat-Beaujon University Hospital, AP-HP - PRES Paris 7 Diderot, Paris, France. · Cancer Research Center of Lyon, INSERM U1052, CNRS 5286, Léon Bérard Center, Claude Bernard Lyon 1 University, Lyon, France. · INSERM UMR1149, Bichat-Beaujon University Hospital, AP-HP - PRES Paris 7 Diderot, Paris, France; Department of Medical Oncology, Curie Institute, Saint Cloud, France. Electronic address: cindy.neuzillet@gmail.com. ·Dig Liver Dis · Pubmed #30205952.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the digestive cancer with the poorest prognosis, with a 5-year overall survival rate of 7%. Complete surgical resection followed by adjuvant chemotherapy is the only treatment with curative intent. However, many patients with an apparently localized disease who may undergo primary tumor resection already have micro-metastatic disease and will promptly develop metastases. Considering the significant rate of morbidity and mortality upon pancreatic surgery, the pre-operative identification of patients with an aggressive disease is therefore a major clinical issue. Although tumor size, differentiation, margins, and lymph node invasion are the main "classical" prognostic factors, they are not sufficient to fully predict early disease recurrence. In the last decade, multi-omics high-throughput analyses have provided a new insight into PDAC biology and have led to the description of multiple molecular subtypes, with a significant prognostic value for most of them, but that have not yet been transposed to routine clinical practice, mainly due to poor availability of tumor tissue material prior to surgical resection. In this review, we provide an overview of the current status of clinico-pathological and molecular biomarkers (tumor and blood) to predict early recurrence, and their implications for clinical practice and future research development.

2 Review Immune therapies in pancreatic ductal adenocarcinoma: Where are we now? 2018

Hilmi, Marc / Bartholin, Laurent / Neuzillet, Cindy. ·Service d'Oncologie Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil 94010, France. · Université de Lyon, Université Claude Bernard Lyon 1, Inserm U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon 69008, France. · Service d'Oncologie Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil 94010, France. cindy.neuzillet@gmail.com. ·World J Gastroenterol · Pubmed #29853732.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, mostly due to its resistance to treatment. Of these, checkpoint inhibitors (CPI) are inefficient when used as monotherapy, except in the case of a rare subset of tumors harboring microsatellite instability (< 2%). This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC. The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancer-associated-fibroblast activation and transforming growth factor β secretion. Several strategies have recently been developed to overcome this immunosuppressive microenvironment. Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells. Ongoing studies are therefore exploring the association of CPI with vaccines, oncolytic viruses, MEK inhibitors, cytokine inhibitors, and hypoxia- and stroma-targeting agents. Adoptive T-cell transfer is also under investigation. Moreover, translational studies on tumor tissue and blood, prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

3 Article Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution. 2016

Le Calvé, Benjamin / Griveau, Audrey / Vindrieux, David / Maréchal, Raphaël / Wiel, Clotilde / Svrcek, Magali / Gout, Johann / Azzi, Lamia / Payen, Léa / Cros, Jérôme / de la Fouchardière, Christelle / Dubus, Pierre / Guitton, Jérôme / Bartholin, Laurent / Bachet, Jean-Baptiste / Bernard, David. ·Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France. · CNRS UMR5286, Lyon, France. · Centre Léon Bérard, Lyon, France. · Université de Lyon, Lyon, France. · Present address: URBC-NARILIS, University of Namur, Namur, Belgium. · Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Belgium. · Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Saint-Antoine Hospital, Paris, France. · Sorbonne University, UPMC University, Paris, France. · Service de Biologie des Tumeurs, CHU de Bordeaux Hôpital du Haut Lévêque, Pessac, France. · Hospices Civils de Lyon, Université de Lyon, Lyon, France. · AP-HP, Hôpitaux Universitaires Paris Nord Val de Seine, Beaujon, France. · Paris Diderot University, Paris, France. · Sorbonne University, UPMC University and INSERM, UMRS 1147, Paris Descrates University, Paris, France. · Gastroenterology Department, APHP, Pitié Salpêtrière Hospital, Paris, France. ·Oncotarget · Pubmed #27050073.

ABSTRACT: Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant "Gemcitabine-based chemotherapy" benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.

4 Article TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma. 2016

Thakur, A K / Nigri, J / Lac, S / Leca, J / Bressy, C / Berthezene, P / Bartholin, L / Chan, P / Calvo, E / Iovanna, J L / Vasseur, S / Guillaumond, F / Tomasini, R. ·CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France. · CRCL, INSERM, U1052; CNRS 5286, Centre Léon Bérard, Lyon, France. · PISSARO Proteomic facility, (IRIB), U-Rouen, Mont Saint- Aignan, France. · Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, Canada. ·Cell Death Differ · Pubmed #26943320.

ABSTRACT: Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

5 Article Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis. 2014

Cano, Carla E / Hamidi, Tewfik / Garcia, Maria Noé / Grasso, Daniel / Loncle, Céline / Garcia, Stéphane / Calvo, Ezequiel / Lomberk, Gwen / Dusetti, Nelson / Bartholin, Laurent / Urrutia, Raul / Iovanna, Juan L. ·Centre de Recherche en Carcérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille University and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, , Marseille, France. ·Gut · Pubmed #24026351.

ABSTRACT: BACKGROUND: Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for Kras(G12D)-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer. METHODS: We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-Kras(G12D);Ink4a/Arf(fl/fl)(KIC) mice. RESULTS: Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1(wt);KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1(wt);KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1(wt);KIC cells. Moreover, Nupr1-deficient and Nurpr1(wt);KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness. CONCLUSIONS: According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.

6 Article Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis. 2013

Wiel, C / Augert, A / Vincent, D F / Gitenay, D / Vindrieux, D / Le Calvé, B / Arfi, V / Lallet-Daher, H / Reynaud, C / Treilleux, I / Bartholin, L / Lelievre, E / Bernard, D. ·1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon [2] CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon [3] Centre Léon Bérard [4] Université de Lyon, Lyon, France. ·Cell Death Dis · Pubmed #24113189.

ABSTRACT: Cellular senescence, a stable proliferation arrest, is induced in response to various stresses. Oncogenic stress-induced senescence (OIS) results in blocked proliferation and constitutes a fail-safe program counteracting tumorigenesis. The events that enable a tumor in a benign senescent state to escape from OIS and become malignant are largely unknown. We show that lysyl oxidase activity contributes to the decision to maintain senescence. Indeed, in human epithelial cell the constitutive expression of the LOX or LOXL2 protein favored OIS escape, whereas inhibition of lysyl oxidase activity was found to stabilize OIS. The relevance of these in vitro observations is supported by in vivo findings: in a transgenic mouse model of aggressive pancreatic ductal adenocarcinoma (PDAC), increasing lysyl oxidase activity accelerates senescence escape, whereas inhibition of lysyl oxidase activity was found to stabilize senescence, delay tumorigenesis, and increase survival. Mechanistically, we show that lysyl oxidase activity favors the escape of senescence by regulating the focal-adhesion kinase. Altogether, our results demonstrate that lysyl oxidase activity participates in primary tumor growth by directly impacting the senescence stability.

7 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.

8 Article Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer. 2012

Cano, Carla E / Sandí, María José / Hamidi, Tewfik / Calvo, Ezequiel L / Turrini, Olivier / Bartholin, Laurent / Loncle, Céline / Secq, Véronique / Garcia, Stéphane / Lomberk, Gwen / Kroemer, Guido / Urrutia, Raul / Iovanna, Juan L. ·INSERM U, CRCM, Cell Stress, Marseille, France. ·EMBO Mol Med · Pubmed #22821859.

ABSTRACT: Pancreatic adenocarcinoma (PDAC) is an extremely deadly disease for which all treatments available have failed to improve life expectancy significantly. This may be explained by the high metastatic potential of PDAC cells, which results from their dedifferentiation towards a mesenchymal phenotype. Some PDAC present cell-in-cell structures whose origin and significance are currently unknown. We show here that cell-in-cells form after homotypic cell cannibalism (HoCC). We found PDAC patients whose tumours display HoCC develop less metastasis than those without. In vitro, HoCC was promoted by inactivation of the nuclear protein 1 (Nupr1), and was enhanced by treatment with transforming growth factor β. HoCC ends with death of PDAC cells, consistent with a metastasis suppressor role for this phenomenon. Hence, our data indicates a protective role for HoCC in PDAC and identifies Nupr1 as a molecular regulator of this process.

9 Article Tif1γ suppresses murine pancreatic tumoral transformation by a Smad4-independent pathway. 2012

Vincent, David F / Gout, Johann / Chuvin, Nicolas / Arfi, Vanessa / Pommier, Roxane M / Bertolino, Philippe / Jonckheere, Nicolas / Ripoche, Doriane / Kaniewski, Bastien / Martel, Sylvie / Langlois, Jean-Baptiste / Goddard-Léon, Sophie / Colombe, Amélie / Janier, Marc / Van Seuningen, Isabelle / Losson, Régine / Valcourt, Ulrich / Treilleux, Isabelle / Dubus, Pierre / Bardeesy, Nabeel / Bartholin, Laurent. ·INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France. ·Am J Pathol · Pubmed #22469842.

ABSTRACT: Transcriptional intermediary factor 1γ (TIF1γ; alias, TRIM33/RFG7/PTC7/ectodermin) belongs to an evolutionarily conserved family of nuclear factors that have been implicated in stem cell pluripotency, embryonic development, and tumor suppression. TIF1γ expression is markedly down-regulated in human pancreatic tumors, and Pdx1-driven Tif1γ inactivation cooperates with the Kras(G12D) oncogene in the mouse pancreas to induce intraductal papillary mucinous neoplasms. In this study, we report that aged Pdx1-Cre; LSL-Kras(G12D); Tif1γ(lox/lox) mice develop pancreatic ductal adenocarcinomas (PDACs), an aggressive and always fatal neoplasm, demonstrating a Tif1γ tumor-suppressive function in the development of pancreatic carcinogenesis. Deletion of SMAD4/DPC4 (deleted in pancreatic carcinoma locus 4) occurs in approximately 50% of human cases of PDAC. We, therefore, assessed the genetic relationship between Tif1γ and Smad4 signaling in pancreatic tumors and found that Pdx1-Cre; LSL-Kras(G12D); Smad4(lox/lox); Tif1γ(lox/lox) (alias, KSSTT) mutant mice exhibit accelerated tumor progression. Consequently, Tif1γ tumor-suppressor effects during progression from a premalignant to a malignant state in our mouse model of pancreatic cancer are independent of Smad4. These findings establish, for the first time to our knowledge, that Tif1γ and Smad4 both regulate an intraductal papillary mucinous neoplasm-to-PDAC sequence through distinct tumor-suppressor programs.