7 results on '"José Courty"'
Search Results
2. Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression
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Matteo Ponzo, Anais Debesset, Mélissande Cossutta, Mounira Chalabi-Dchar, Claire Houppe, Caroline Pilon, Alba Nicolas-Boluda, Sylvain Meunier, Fabio Raineri, Allan Thiolat, Rémy Nicolle, Federica Maione, Serena Brundu, Carina Florina Cojocaru, Philippe Bouvet, Corinne Bousquet, Florence Gazeau, Christophe Tournigand, José Courty, Enrico Giraudo, José L. Cohen, and Ilaria Cascone
- Subjects
vessels ,nucleolin ,immune cells ,PDAC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.
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- 2022
- Full Text
- View/download PDF
3. Nucleolin Aptamer N6L Reprograms the Translational Machinery and Acts Synergistically with mTORi to Inhibit Pancreatic Cancer Proliferation
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Mounira Chalabi-Dchar, Elisabeth Cruz, Hichem C. Mertani, Jean-Jacques Diaz, José Courty, Ilaria Cascone, and Philippe Bouvet
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nucleolin ,pancreatic cancer ,translation ,mTOR inhibitor ,combotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5′TOP motif in many of these mRNAs and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and tumor-derived organoids, was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.
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- 2021
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4. The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options
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Benedetta Ferrara, Cataldo Pignatelli, Mélissande Cossutta, Antonio Citro, José Courty, and Lorenzo Piemonti
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extracellular matrix ,stroma ,stiffness ,solid stress ,matrix remodeling ,cancer-associated fibroblasts ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.
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- 2021
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5. Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma
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Fabio Raineri, Sandrine Bourgoin-Voillard, Mélissande Cossutta, Damien Habert, Matteo Ponzo, Claire Houppe, Benoît Vallée, Michele Boniotto, Mounira Chalabi-Dchar, Philippe Bouvet, Anne Couvelard, Jerome Cros, Anais Debesset, José L. Cohen, José Courty, and Ilaria Cascone
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pancreatic ductal adenocarcinoma ,nucleolin ,N6L ,Wnt/β-catenin pathway ,tumor microenvironment ,cancer therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.
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- 2021
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6. Iron Oxide Nanoparticles as Carriers for DOX and Magnetic Hyperthermia after Intratumoral Application into Breast Cancer in Mice: Impact and Future Perspectives
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Susann Piehler, Heidi Dähring, Julia Grandke, Julia Göring, Pierre Couleaud, Antonio Aires, Aitziber L. Cortajarena, José Courty, Alfonso Latorre, Álvaro Somoza, Ulf Teichgräber, and Ingrid Hilger
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magnetic hyperthermia ,magnetic nanoparticles ,doxorubicin ,breast cancer ,mouse model ,Chemistry ,QD1-999 - Abstract
There is still a need for improving the treatment of breast cancer with doxorubicin (DOX). In this paper, we functionalized magnetic nanoparticles (MNPs) with DOX and studied the DOX-induced antitumor effects in breast cancer cells (BT474) in the presence of magnetic hyperthermia (43 °C, 1 h). We show that i) intratumoral application of DOX-functionalized MNPs (at least at a concentration of 9.6 nmol DOX/100 mm3 tumor volume) combined with magnetic hyperthermia favors tumor regression in vivo, and there is evidence for an increased effect compared to magnetic hyperthermia alone or to the intratumoral application of free DOX and ii) the presence of the pseudopeptide NucAnt (N6L) on the MNP surface might well be beneficial in its function as carrier for MNP internalization into breast cancer cells in vitro, which could further augment the possibility of the induction of intracellular heating spots and cell death in the future.
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- 2020
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- View/download PDF
7. Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma
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José Cohen, Sandrine Bourgoin-Voillard, Philippe Bouvet, Damien Habert, Mounira Chalabi-Dchar, Claire Houppe, Ilaria Cascone, Mélissande Cossutta, Benoît Vallée, José Courty, Matteo Ponzo, Anais Debesset, Jérôme Cros, Fabio Raineri, Michele Boniotto, Anne Couvelard, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and COSSUTTA, Mélissande
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0301 basic medicine ,Cancer Research ,Pancreatic ductal adenocarcinoma ,endocrine system diseases ,pancreatic ductal adenocarcinoma ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Article ,03 medical and health sciences ,nucleolin ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,In vivo ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Wnt/β-catenin pathway ,tumor microenvironment ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RC254-282 ,Loss function ,N6L ,Tumor microenvironment ,Chemistry ,Wnt signaling pathway ,Antagonist ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Catenin ,Cancer research ,cancer therapy ,Nucleolin - Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has no effective treatment. Nucleolin targeting by the pseudopeptide N6L inhibits the tumor growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the pathways regulated by nucleolin and N6L in PDAC. We demonstrated that both interact with β-catenin, and that the Wnt/β-catenin pathway is activated in PDAC mouse models. Nucleolin inhibition decreases Wnt/β-catenin pathway activation in PDAC cells and tumors, and represents a new druggable pathway regulated by nucleolin. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.
- Published
- 2021
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