2019
|
Müller, D; Shin, S; Goullet de Rugy, T; Samain, R; Baer, R; Strehaiano, M; Masvidal-Sanz, L; Guillermet-Guibert, J; Jean, C; Tsukumo, Y; Sonenberg, N; Marion, F; Guilbaud, N; Hoffmann, JS. ; Larsson, O; Bousquet, C; Pyronnet, S; Martineau, Y eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer Article de journal JCI Insight, 4 (21), p. 121951, 2019. Résumé | Liens | BibTeX @article{Müller2019,
title = {eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer},
author = {Müller, D. and Shin, S. and Goullet de Rugy, T. and Samain, R. and Baer, R. and Strehaiano, M. and Masvidal-Sanz, L. and Guillermet-Guibert, J. and Jean, C. and Tsukumo, Y. and Sonenberg, N. and Marion, F. and Guilbaud, N. and Hoffmann, JS. and Larsson, O. and Bousquet, C. and Pyronnet, S. and Martineau, Y.},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948775/},
doi = {10.1172/jci.insight.121951},
year = {2019},
date = {2019-11-01},
journal = {JCI Insight},
volume = {4},
number = {21},
pages = {121951},
abstract = {Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2-deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2-deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition. |
Saponaro, C; Thévenet, J; Gmyr, V; Moerman, E; Delalleau, N; Pasquetti, G; Quenon, A; Daoudi, M; Hubert, T; Vantyghem, MC. ; Bousquet, C; Martineau, Y; Kerr-Conte, J; Staels, B; Pattou, F; Bonner, C The GLP1R Agonist Liraglutide Reduces Hyperglucagonemia Induced by the SGLT2 Inhibitor Dapagliflozin via Somatostatin Release. Article de journal Cell Rep, 28 (6), p. 1447-1454, 2019. Résumé | Liens | BibTeX @article{Saponaro2019,
title = {The GLP1R Agonist Liraglutide Reduces Hyperglucagonemia Induced by the SGLT2 Inhibitor Dapagliflozin via Somatostatin Release.},
author = {Saponaro, C. and Thévenet, J. and Gmyr, V. and Moerman, E. and Delalleau, N. and Pasquetti, G. and Quenon, A. and Daoudi, M. and Hubert, T. and Vantyghem, MC. and Bousquet, C. and Martineau, Y. and Kerr-Conte, J. and Staels, B. and Pattou, F. and Bonner, C.},
editor = {Elsevier},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(19)30899-X},
doi = {10.1016/j.celrep.2019.07.009},
year = {2019},
date = {2019-08-06},
journal = {Cell Rep},
volume = {28},
number = {6},
pages = {1447-1454},
abstract = {The newest classes of anti-diabetic agents include sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor (GLP1R) agonists. The SGLT2 inhibitor dapagliflozin reduces glucotoxicity by glycosuria but elevates glucagon secretion. The GLP1R agonist liraglutide inhibits glucagon; therefore, we hypothesize that the cotreatment of dapagliflozin with liraglutide could reduce hyperglucagonemia and hyperglycemia. Here we use five complementary models: human islet cultures, healthy mice, db/db mice, diet-induced obese (DIO) mice, and somatostatin receptor-2 (SSTR2) KO mice. A single administration of liraglutide and dapagliflozin in combination improves glycemia and reduces dapagliflozin-induced glucagon secretion in diabetic mice. Chronic treatment with liraglutide and dapagliflozin produces a sustainable reduction of glycemia compared with each drug alone. Moreover, liraglutide reduces dapagliflozin-induced glucagon secretion by enhancing somatostatin release, as demonstrated by SSTR2 inhibition in human islets and in mice. Collectively, these data provide mechanistic insights into how intra-islet GLP1R activation is critical for the regulation of glucose homeostasis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The newest classes of anti-diabetic agents include sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor (GLP1R) agonists. The SGLT2 inhibitor dapagliflozin reduces glucotoxicity by glycosuria but elevates glucagon secretion. The GLP1R agonist liraglutide inhibits glucagon; therefore, we hypothesize that the cotreatment of dapagliflozin with liraglutide could reduce hyperglucagonemia and hyperglycemia. Here we use five complementary models: human islet cultures, healthy mice, db/db mice, diet-induced obese (DIO) mice, and somatostatin receptor-2 (SSTR2) KO mice. A single administration of liraglutide and dapagliflozin in combination improves glycemia and reduces dapagliflozin-induced glucagon secretion in diabetic mice. Chronic treatment with liraglutide and dapagliflozin produces a sustainable reduction of glycemia compared with each drug alone. Moreover, liraglutide reduces dapagliflozin-induced glucagon secretion by enhancing somatostatin release, as demonstrated by SSTR2 inhibition in human islets and in mice. Collectively, these data provide mechanistic insights into how intra-islet GLP1R activation is critical for the regulation of glucose homeostasis. |
Neuzillet, C; Tijeras-Raballand, A; Ragulan, C; Cros, J; Patil, Y; Martinet, M; Erkan, M; Kleeff, J; Wilson, J; Apte, M; Tosolini, M; Wilson, AS. ; Delvecchio, FR. ; Bousquet, C; Paradis, V; Hammel, P; Sadanandam, A; Kocher, HM. Inter- and intra-tumoral heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. Article de journal J Pathol, 248 (1), p. 51-65, 2019. Résumé | Liens | BibTeX @article{Neuzillet2019,
title = {Inter- and intra-tumoral heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma.},
author = {Neuzillet, C. and Tijeras-Raballand, A. and Ragulan, C. and Cros, J. and Patil, Y. and Martinet, M. and Erkan, M. and Kleeff, J. and Wilson, J. and Apte, M. and Tosolini, M. and Wilson, AS. and Delvecchio, FR. and Bousquet, C. and Paradis, V. and Hammel, P. and Sadanandam, A. and Kocher, HM.},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492001/},
doi = {10.1002/path.5224},
year = {2019},
date = {2019-05-01},
journal = {J Pathol},
volume = {248},
number = {1},
pages = {51-65},
abstract = {Cancer‐associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro‐ versus anti‐tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient‐derived CAF primary cultures, we demonstrated that human PDAC‐derived CAFs display a high level of inter‐ and intra‐tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC‐derived CAFs (pCAFassigner). Multiple CAF subtypes co‐existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix‐ and immune‐related signatures, vimentin and α‐smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non‐tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF‐like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter‐ and intra‐tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single‐cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cancer‐associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro‐ versus anti‐tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient‐derived CAF primary cultures, we demonstrated that human PDAC‐derived CAFs display a high level of inter‐ and intra‐tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC‐derived CAFs (pCAFassigner). Multiple CAF subtypes co‐existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix‐ and immune‐related signatures, vimentin and α‐smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non‐tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF‐like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter‐ and intra‐tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single‐cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
Goehrig, D; Samain, R; Nigri, J; Wu, Z; Cappello, P; Gabiane, G; Zhang, X; Zhao, Y; Kim, IS. ; Chanal, M; Curto, R; Hervieu, V; de La Fouchardière, C; Novelli, F; Milani, P; Tomasini, R; Bousquet, C; Bertolino, P; Hennino, A Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer. Article de journal Gut, 68 (4), p. 693-707, 2019. Résumé | Liens | BibTeX @article{Goehrig2019,
title = {Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer.},
author = {Goehrig, D. and Samain, R. and Nigri, J. and Wu, Z. and Cappello, P. and Gabiane, G. and Zhang, X. and Zhao, Y. and Kim, IS. and Chanal, M. and Curto, R. and Hervieu, V. and de La Fouchardière, C. and Novelli, F. and Milani, P. and Tomasini, R. and Bousquet, C. and Bertolino, P. and Hennino, A. },
url = {https://gut.bmj.com/content/68/4/693.long},
doi = {10.1136/gutjnl-2018-317570},
year = {2019},
date = {2019-04-01},
journal = {Gut},
volume = {68},
number = {4},
pages = {693-707},
abstract = {OBJECTIVE:
Pancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.
DESIGN:
We performed studies with p48-Cre;Kras G12D, pdx1-Cre;KrasG12D;Ink4a/Arf fl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.
RESULTS:
We identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.
CONCLUSIONS:
Our data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE:
Pancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.
DESIGN:
We performed studies with p48-Cre;Kras G12D, pdx1-Cre;KrasG12D;Ink4a/Arf fl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.
RESULTS:
We identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.
CONCLUSIONS:
Our data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer. |
2018
|
Günther, T; Tulipano, G; Dournaud, P; Bousquet, C; Csaba, Z; Kreienkamp, HJ. ; Lupp, A; Korbonits, M; Castaño, JP. ; Wester, HJ. ; Culler, M; Melmed, S; Schulz, S International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Article de journal Pharmacoil Rev, 70 (4), p. 763-835, 2018. Résumé | Liens | BibTeX @article{Günther2018,
title = {International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.},
author = {Günther, T. and Tulipano, G. and Dournaud, P. and Bousquet, C. and Csaba, Z. and Kreienkamp, HJ. and Lupp, A. and Korbonits, M. and Castaño, JP. and Wester, HJ. and Culler, M. and Melmed, S. and Schulz, S.},
url = {http://pharmrev.aspetjournals.org/content/70/4/763.long},
doi = {10.1124/pr.117.015388},
year = {2018},
date = {2018-10-01},
journal = {Pharmacoil Rev},
volume = {70},
number = {4},
pages = {763-835},
abstract = {Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature. |
Ogier, C; Colombo, PE. ; Bousquet, C; Canterel-Thouennon, L; Sicard, P; Garambois, V; Thomas, G; Gaborit, N; Jarlier, M; Pirot, N; Pugnière, M; Vie, N; Gongora, C; Martineau, P; Robert, B; Pèlegrin, A; Chardès, T; Larbouret, C Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer. Article de journal Cancer lett, 432 , p. 227-236, 2018. Résumé | Liens | BibTeX @article{Ogier2018,
title = {Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer.},
author = {Ogier, C. and Colombo, PE. and Bousquet, C. and Canterel-Thouennon, L. and Sicard, P. and Garambois, V. and Thomas, G. and Gaborit, N. and Jarlier, M. and Pirot, N. and Pugnière, M. and Vie, N. and Gongora, C. and Martineau, P. and Robert, B. and Pèlegrin, A. and Chardès, T. and Larbouret, C.},
editor = {Elsevier},
url = {Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation. To do so, we demonstrated the promising tumor growth inhibitory effect of the 7E3, an original antibody directed to NRG1. This antibody promotes antibody dependent cellular cytotoxicity in NRG1-positive PC and CAFs and inhibits NRG1-associated signaling pathway induction, by blocking NRG1-mediated HER3 activation. Moreover, 7E3 inhibits migration and growth of pancreatic cancer cells co-cultured with CAFs, both in vitro and in vivo using orthotopic pancreatic tumor xenografts. Our preclinical results demonstrate that the anti-NRG1 antibody 7E3 could represent a promising approach to target pancreatic stroma and cancer cells, thereby providing novel therapeutic options for PDAC.},
doi = {10.1016/j.canlet.2018.06.023},
year = {2018},
date = {2018-09-28},
journal = {Cancer lett},
volume = {432},
pages = {227-236},
abstract = {Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation. To do so, we demonstrated the promising tumor growth inhibitory effect of the 7E3, an original antibody directed to NRG1. This antibody promotes antibody dependent cellular cytotoxicity in NRG1-positive PC and CAFs and inhibits NRG1-associated signaling pathway induction, by blocking NRG1-mediated HER3 activation. Moreover, 7E3 inhibits migration and growth of pancreatic cancer cells co-cultured with CAFs, both in vitro and in vivo using orthotopic pancreatic tumor xenografts. Our preclinical results demonstrate that the anti-NRG1 antibody 7E3 could represent a promising approach to target pancreatic stroma and cancer cells, thereby providing novel therapeutic options for PDAC.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation. To do so, we demonstrated the promising tumor growth inhibitory effect of the 7E3, an original antibody directed to NRG1. This antibody promotes antibody dependent cellular cytotoxicity in NRG1-positive PC and CAFs and inhibits NRG1-associated signaling pathway induction, by blocking NRG1-mediated HER3 activation. Moreover, 7E3 inhibits migration and growth of pancreatic cancer cells co-cultured with CAFs, both in vitro and in vivo using orthotopic pancreatic tumor xenografts. Our preclinical results demonstrate that the anti-NRG1 antibody 7E3 could represent a promising approach to target pancreatic stroma and cancer cells, thereby providing novel therapeutic options for PDAC. |
2017
|
Elia, A; Henry-Grant, R; Adiseshiah, C; Marboeuf, C; Buckley, RJ. ; Clemens, MJ. ; Mudan, S; Pyronnet, S Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL Article de journal Cell Death and Dis, (8), p. 3204, 2017. Résumé | Liens | BibTeX @article{Elia2017,
title = {Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL},
author = {Elia, A. and Henry-Grant, R. and Adiseshiah, C. and Marboeuf, C. and Buckley, RJ. and Clemens, MJ. and Mudan, S. and Pyronnet, S.},
url = {https://www.nature.com/articles/s41419-017-0001-z},
doi = {10.1038/s41419-017-0001-z},
year = {2017},
date = {2017-12-12},
journal = {Cell Death and Dis},
number = {8},
pages = {3204},
abstract = {Pancreatic cancer cells show varying sensitivity to the anticancer effects of gemcitabine. However, as a chemotherapeutic agent, gemcitabine can cause intolerably high levels of toxicity and patients often develop resistance to the beneficial effects of this drug. Combination studies show that use of gemcitabine with the pro-apoptotic cytokine TRAIL can enhance the inhibition of survival and induction of apoptosis of pancreatic cancer cells. Additionally, following combination treatment there is a dramatic increase in the level of the hypophosphorylated form of the tumour suppressor protein 4E-BP1. This is associated with inhibition of mTOR activity, resulting from caspase-mediated cleavage of the Raptor and Rictor components of mTOR. Use of the pan-caspase inhibitor Z-VAD-FMK indicates that the increase in level of 4E-BP1 is also caspase-mediated. ShRNA-silencing of 4E-BP1 expression renders cells more resistant to cell death induced by the combination treatment. Since the levels of 4E-BP1 are relatively low in untreated pancreatic cancer cells these results suggest that combined therapy with gemcitabine and TRAIL could improve the responsiveness of tumours to treatment by elevating the expression of 4E-BP1.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pancreatic cancer cells show varying sensitivity to the anticancer effects of gemcitabine. However, as a chemotherapeutic agent, gemcitabine can cause intolerably high levels of toxicity and patients often develop resistance to the beneficial effects of this drug. Combination studies show that use of gemcitabine with the pro-apoptotic cytokine TRAIL can enhance the inhibition of survival and induction of apoptosis of pancreatic cancer cells. Additionally, following combination treatment there is a dramatic increase in the level of the hypophosphorylated form of the tumour suppressor protein 4E-BP1. This is associated with inhibition of mTOR activity, resulting from caspase-mediated cleavage of the Raptor and Rictor components of mTOR. Use of the pan-caspase inhibitor Z-VAD-FMK indicates that the increase in level of 4E-BP1 is also caspase-mediated. ShRNA-silencing of 4E-BP1 expression renders cells more resistant to cell death induced by the combination treatment. Since the levels of 4E-BP1 are relatively low in untreated pancreatic cancer cells these results suggest that combined therapy with gemcitabine and TRAIL could improve the responsiveness of tumours to treatment by elevating the expression of 4E-BP1. |
2016
|
Moatassim-Billah, S; Duluc, C; Samain, R; Jean, C; Perraud, A; Decaup, E; Cassant-Sourdy, S; Bakri, Y; Selves, J; Schmid, H; Martineau, Y; Mathonnet, M; Pyronnet, S; Bousquet, C Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts Article de journal Oncotarget, 7 (27), p. 41584-41598, 2016, ISSN: 1949-2553 (Electronic)
1949-2553 (Linking). Liens | BibTeX @article{RN1b,
title = {Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts},
author = {Moatassim-Billah, S. and Duluc, C. and Samain, R. and Jean, C. and Perraud, A. and Decaup, E. and Cassant-Sourdy, S. and Bakri, Y. and Selves, J. and Schmid, H. and Martineau, Y. and Mathonnet, M. and Pyronnet, S. and Bousquet, C.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27177087},
doi = {10.18632/oncotarget.9296},
issn = {1949-2553 (Electronic)
1949-2553 (Linking)},
year = {2016},
date = {2016-01-01},
journal = {Oncotarget},
volume = {7},
number = {27},
pages = {41584-41598},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2015
|
Chalabi-Dchar, M; Cassant-Sourdy, S; Duluc, C; Fanjul, M; Lulka, H; Samain, R; Roche, C; Breibach, F; Delisle, M B; Poupot, M; Dufresne, M; Shimaoka, T; Yonehara, S; Mathonnet, M; Pyronnet, S; Bousquet, C Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-Induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16 Article de journal Gastroenterology, 148 (7), p. 1452-65, 2015, ISSN: 1528-0012 (Electronic)
0016-5085 (Linking). Liens | BibTeX @article{RN3b,
title = {Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-Induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16},
author = {Chalabi-Dchar, M. and Cassant-Sourdy, S. and Duluc, C. and Fanjul, M. and Lulka, H. and Samain, R. and Roche, C. and Breibach, F. and Delisle, M. B. and Poupot, M. and Dufresne, M. and Shimaoka, T. and Yonehara, S. and Mathonnet, M. and Pyronnet, S. and Bousquet, C.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25683115},
doi = {10.1053/j.gastro.2015.02.009},
issn = {1528-0012 (Electronic)
0016-5085 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {Gastroenterology},
volume = {148},
number = {7},
pages = {1452-65},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Duluc, C; Moatassim-Billah, S; Chalabi-Dchar, M; Perraud, A; Samain, R; Breibach, F; Gayral, M; Cordelier, P; Delisle, M B; Bousquet-Dubouch, M P; Tomasini, R; Schmid, H; Mathonnet, M; Pyronnet, S; Martineau, Y; Bousquet, C Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance Article de journal EMBO Mol Med, 7 (6), p. 735-53, 2015, ISSN: 1757-4684 (Electronic)
1757-4676 (Linking). Liens | BibTeX @article{RN2b,
title = {Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance},
author = {Duluc, C. and Moatassim-Billah, S. and Chalabi-Dchar, M. and Perraud, A. and Samain, R. and Breibach, F. and Gayral, M. and Cordelier, P. and Delisle, M. B. and Bousquet-Dubouch, M. P. and Tomasini, R. and Schmid, H. and Mathonnet, M. and Pyronnet, S. and Martineau, Y. and Bousquet, C.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25834145},
doi = {10.15252/emmm.201404346},
issn = {1757-4684 (Electronic)
1757-4676 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {EMBO Mol Med},
volume = {7},
number = {6},
pages = {735-53},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2014
|
Laval, S; Laklai, H; Fanjul, M; Pucelle, M; Laurell, H; Billon-Gales, A; Le Guellec, S; Delisle, M B; Sonnenberg, A; Susini, C; Pyronnet, S; Bousquet, C Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides Article de journal Oncogene, 33 (15), p. 1934-44, 2014, ISSN: 1476-5594 (Electronic)
0950-9232 (Linking). Liens | BibTeX @article{RN5b,
title = {Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides},
author = {Laval, S. and Laklai, H. and Fanjul, M. and Pucelle, M. and Laurell, H. and Billon-Gales, A. and Le Guellec, S. and Delisle, M. B. and Sonnenberg, A. and Susini, C. and Pyronnet, S. and Bousquet, C.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23624916},
doi = {10.1038/onc.2013.146},
issn = {1476-5594 (Electronic)
0950-9232 (Linking)},
year = {2014},
date = {2014-01-01},
journal = {Oncogene},
volume = {33},
number = {15},
pages = {1934-44},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Martineau, Y; Azar, R; Muller, D; Lasfargues, C; El Khawand, S; Anesia, R; Pelletier, J; Bousquet, C; Pyronnet, S Pancreatic tumours escape from translational control through 4E-BP1 loss Article de journal Oncogene, 33 (11), p. 1367-74, 2014, ISSN: 1476-5594 (Electronic)
0950-9232 (Linking). Liens | BibTeX @article{RN4b,
title = {Pancreatic tumours escape from translational control through 4E-BP1 loss},
author = {Martineau, Y. and Azar, R. and Muller, D. and Lasfargues, C. and El Khawand, S. and Anesia, R. and Pelletier, J. and Bousquet, C. and Pyronnet, S.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23563181},
doi = {10.1038/onc.2013.100},
issn = {1476-5594 (Electronic)
0950-9232 (Linking)},
year = {2014},
date = {2014-01-01},
journal = {Oncogene},
volume = {33},
number = {11},
pages = {1367-74},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2013
|
Martineau, Y; Azar, R; Bousquet, C; Pyronnet, S Anti-oncogenic potential of the eIF4E-binding proteins Article de journal Oncogene, 32 (6), p. 671-7, 2013, ISSN: 1476-5594 (Electronic)
0950-9232 (Linking). Liens | BibTeX @article{RN6b,
title = {Anti-oncogenic potential of the eIF4E-binding proteins},
author = {Martineau, Y. and Azar, R. and Bousquet, C. and Pyronnet, S.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/22508483},
doi = {10.1038/onc.2012.116},
issn = {1476-5594 (Electronic)
0950-9232 (Linking)},
year = {2013},
date = {2013-01-01},
journal = {Oncogene},
volume = {32},
number = {6},
pages = {671-7},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2012
|
Najib, S; Saint-Laurent, N; Esteve, J P; Schulz, S; Boutet-Robinet, E; Fourmy, D; Lattig, J; Mollereau, C; Pyronnet, S; Susini, C; Bousquet, C A switch of G protein-coupled receptor binding preference from phosphoinositide 3-kinase (PI3K)-p85 to filamin A negatively controls the PI3K pathway Article de journal Mol Cell Biol, 32 (5), p. 1004-16, 2012, ISSN: 1098-5549 (Electronic)
0270-7306 (Linking). Liens | BibTeX @article{RN7b,
title = {A switch of G protein-coupled receptor binding preference from phosphoinositide 3-kinase (PI3K)-p85 to filamin A negatively controls the PI3K pathway},
author = {Najib, S. and Saint-Laurent, N. and Esteve, J. P. and Schulz, S. and Boutet-Robinet, E. and Fourmy, D. and Lattig, J. and Mollereau, C. and Pyronnet, S. and Susini, C. and Bousquet, C.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/22203038},
doi = {10.1128/MCB.06252-11},
issn = {1098-5549 (Electronic)
0270-7306 (Linking)},
year = {2012},
date = {2012-01-01},
journal = {Mol Cell Biol},
volume = {32},
number = {5},
pages = {1004-16},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2010
|
Alard, A; Fabre, B; Anesia, R; Marboeuf, C; Pierre, P; Susini, C; Bousquet, C; Pyronnet, S NAD(P)H quinone-oxydoreductase 1 protects eukaryotic translation initiation factor 4GI from degradation by the proteasome Article de journal Mol Cell Biol, 30 (4), p. 1097-105, 2010, ISSN: 1098-5549 (Electronic)
0270-7306 (Linking). Liens | BibTeX @article{RN8b,
title = {NAD(P)H quinone-oxydoreductase 1 protects eukaryotic translation initiation factor 4GI from degradation by the proteasome},
author = {Alard, A. and Fabre, B. and Anesia, R. and Marboeuf, C. and Pierre, P. and Susini, C. and Bousquet, C. and Pyronnet, S.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20028737},
doi = {10.1128/MCB.00868-09},
issn = {1098-5549 (Electronic)
0270-7306 (Linking)},
year = {2010},
date = {2010-01-01},
journal = {Mol Cell Biol},
volume = {30},
number = {4},
pages = {1097-105},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2009
|
Azar, R; Alard, A; Susini, C; Bousquet, C; Pyronnet, S 4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation Article de journal EMBO J, 28 (22), p. 3514-22, 2009, ISSN: 1460-2075 (Electronic)
0261-4189 (Linking). Liens | BibTeX @article{RN10b,
title = {4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation},
author = {Azar, R. and Alard, A. and Susini, C. and Bousquet, C. and Pyronnet, S.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19834456},
doi = {10.1038/emboj.2009.291},
issn = {1460-2075 (Electronic)
0261-4189 (Linking)},
year = {2009},
date = {2009-01-01},
journal = {EMBO J},
volume = {28},
number = {22},
pages = {3514-22},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Laklai, H; Laval, S; Dumartin, L; Rochaix, P; Hagedorn, M; Bikfalvi, A; Le Guellec, S; Delisle, M B; Schally, A V; Susini, C; Pyronnet, S; Bousquet, C Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer Article de journal Proc Natl Acad Sci U S A, 106 (42), p. 17769-74, 2009, ISSN: 1091-6490 (Electronic)
0027-8424 (Linking). Liens | BibTeX @article{RN9b,
title = {Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer},
author = {Laklai, H. and Laval, S. and Dumartin, L. and Rochaix, P. and Hagedorn, M. and Bikfalvi, A. and Le Guellec, S. and Delisle, M. B. and Schally, A. V. and Susini, C. and Pyronnet, S. and Bousquet, C.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19805200},
doi = {10.1073/pnas.0908674106},
issn = {1091-6490 (Electronic)
0027-8424 (Linking)},
year = {2009},
date = {2009-01-01},
journal = {Proc Natl Acad Sci U S A},
volume = {106},
number = {42},
pages = {17769-74},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
