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  1. Article ; Online: Semi-supervised analysis of myeloid and T cell behavior in

    Laforêts, Florian / Kotantaki, Panoraia / Malacrida, Beatrice / Elorbany, Samar / Manchanda, Ranjit / Donnadieu, Emmanuel / Balkwill, Frances

    iScience

    2023  Volume 26, Issue 4, Page(s) 106514

    Abstract: Studies of the high-grade serous ovarian cancer (HGSOC) tumor microenvironment, the most lethal gynecological cancer, aim to enhance the efficiency of established therapies. Cell motility is an important process of anti-tumor response. ... ...

    Abstract Studies of the high-grade serous ovarian cancer (HGSOC) tumor microenvironment, the most lethal gynecological cancer, aim to enhance the efficiency of established therapies. Cell motility is an important process of anti-tumor response. Using
    Language English
    Publishing date 2023-03-29
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2023.106514
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer.

    Gopinathan, Ganga / Berlato, Chiara / Lakhani, Anissa / Szabova, Ludmila / Pegrum, Colin / Pedrosa, Ana-Rita / Laforets, Florian / Maniati, Eleni / Balkwill, Frances R

    Molecular cancer therapeutics

    2022  Volume 21, Issue 6, Page(s) 1030–1043

    Abstract: This article investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer (HGSOC), and defines rational combination therapies. We used three different syngeneic orthotopic mouse HGSOC models that ... ...

    Abstract This article investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer (HGSOC), and defines rational combination therapies. We used three different syngeneic orthotopic mouse HGSOC models that replicated the human tumor microenvironment (TME). After 4 to 5 weeks treatment of established tumors, cediranib had antitumor activity with increased tumor T-cell infiltrates and alterations in myeloid cells. However, continued cediranib treatment did not change overall survival or the immune microenvironment in two of the three models. Moreover, treated mice developed additional peritoneal metastases not seen in controls. Cediranib-resistant tumors had intrinsically high levels of IL6 and JAK/STAT signaling and treatment increased endothelial STAT3 activation. Combination of cediranib with a murine anti-IL6 antibody was superior to monotherapy, increasing mouse survival, reducing blood vessel density, and pSTAT3, with increased T-cell infiltrates in both models. In a third HGSOC model, that had lower inherent IL6 JAK/STAT3 signaling in the TME but high programmed cell death protein 1 (PD-1) signaling, long-term cediranib treatment significantly increased overall survival. When the mice eventually relapsed, pSTAT3 was still reduced in the tumors but there were high levels of immune cell PD-1 and Programmed death-ligand 1. Combining cediranib with an anti-PD-1 antibody was superior to monotherapy in this model, increasing T cells and decreasing blood vessel densities. Bioinformatics analysis of two human HGSOC transcriptional datasets revealed distinct clusters of tumors with IL6 and PD-1 pathway expression patterns that replicated the mouse tumors. Combination of anti-IL6 or anti-PD-1 in these patients may increase activity of VEGFR inhibitors and prolong disease-free survival.
    MeSH term(s) Angiogenesis Inhibitors/pharmacology ; Animals ; Carcinoma, Ovarian Epithelial ; Cell Line, Tumor ; Female ; Humans ; Indoles ; Interleukin-6 ; Mice ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Programmed Cell Death 1 Receptor ; Quinazolines ; Tumor Microenvironment
    Chemical Substances Angiogenesis Inhibitors ; Indoles ; Interleukin-6 ; Programmed Cell Death 1 Receptor ; Quinazolines ; cediranib (NQU9IPY4K9)
    Language English
    Publishing date 2022-03-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-21-0689
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  3. Article ; Online: The Tumor Microenvironment of Clear-Cell Ovarian Cancer.

    Devlin, Michael-John / Miller, Rowan / Laforets, Florian / Kotantaki, Panoraia / Garsed, Dale W / Kristeleit, Rebecca / Bowtell, David D / McDermott, Jacqueline / Maniati, Eleni / Balkwill, Frances R

    Cancer immunology research

    2022  Volume 10, Issue 11, Page(s) 1326–1339

    Abstract: Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical ... ...

    Abstract Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of ARID1A-wildtype (ARID1Awt) versus ARID1A-mutant (ARID1Amut) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138+ plasma cells, the LE had more CD20+ B cells and T cells, whereas the stroma had more mast cells and αSMA+ fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating "TGFβ remodeling of the extracellular matrix" as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1Awt and ARID1Amut CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8+ T cells within the MCA and CD4+ T cells at the LE and stroma significantly associated with decreased overall survival.
    MeSH term(s) Female ; Humans ; Tumor Microenvironment ; Programmed Cell Death 1 Receptor ; CD8-Positive T-Lymphocytes ; Ovarian Neoplasms/pathology ; Collagen
    Chemical Substances Programmed Cell Death 1 Receptor ; Collagen (9007-34-5)
    Language English
    Publishing date 2022-10-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2732489-8
    ISSN 2326-6074 ; 2326-6066
    ISSN (online) 2326-6074
    ISSN 2326-6066
    DOI 10.1158/2326-6066.CIR-22-0407
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7022: Show issues Location:
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  4. Article ; Online: Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance.

    Therizols, Gabriel / Bash-Imam, Zeina / Panthu, Baptiste / Machon, Christelle / Vincent, Anne / Ripoll, Julie / Nait-Slimane, Sophie / Chalabi-Dchar, Mounira / Gaucherot, Angéline / Garcia, Maxime / Laforêts, Florian / Marcel, Virginie / Boubaker-Vitre, Jihane / Monet, Marie-Ambre / Bouclier, Céline / Vanbelle, Christophe / Souahlia, Guillaume / Berthel, Elise / Albaret, Marie Alexandra /
    Mertani, Hichem C / Prudhomme, Michel / Bertrand, Martin / David, Alexandre / Saurin, Jean-Christophe / Bouvet, Philippe / Rivals, Eric / Ohlmann, Théophile / Guitton, Jérôme / Dalla Venezia, Nicole / Pannequin, Julie / Catez, Frédéric / Diaz, Jean-Jacques

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 173

    Abstract: Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor ... ...

    Abstract Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.
    MeSH term(s) Antimetabolites, Antineoplastic/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; DNA Replication ; DNA, Neoplasm/genetics ; DNA, Neoplasm/metabolism ; Drug Resistance, Neoplasm/genetics ; Drug Tolerance/genetics ; Fluorouracil/pharmacology ; HCT116 Cells ; Halogenation ; Humans ; Protein Biosynthesis/drug effects ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Ribosomal/genetics ; RNA, Ribosomal/metabolism ; Receptor, IGF Type 1/agonists ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; Ribosomes/drug effects ; Ribosomes/genetics ; Ribosomes/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Antimetabolites, Antineoplastic ; DNA, Neoplasm ; RNA, Messenger ; RNA, Ribosomal ; Receptor, IGF Type 1 (EC 2.7.10.1) ; Fluorouracil (U3P01618RT)
    Language English
    Publishing date 2022-01-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-27847-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism.

    Bash-Imam, Zeina / Thérizols, Gabriel / Vincent, Anne / Lafôrets, Florian / Polay Espinoza, Micaela / Pion, Nathalie / Macari, Françoise / Pannequin, Julie / David, Alexandre / Saurin, Jean-Christophe / Mertani, Hichem C / Textoris, Julien / Auboeuf, Didier / Catez, Frédéric / Dalla Venezia, Nicole / Dutertre, Martin / Marcel, Virginie / Diaz, Jean-Jacques

    Oncotarget

    2017  Volume 8, Issue 28, Page(s) 46219–46233

    Abstract: 5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the ... ...

    Abstract 5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the translational machinery and that 5-FU affects the amount of some mRNAs associated with ribosomes. However, the impact of 5-FU on translational regulation remains unclear. Using translatome profiling, we report that a clinically relevant dose of 5-FU induces a translational reprogramming in colorectal cancer cell lines. Comparison of mRNA distribution between polysomal and non-polysomal fractions in response to 5-FU treatment using microarray quantification identified 313 genes whose translation was selectively regulated. These regulations were mostly stimulatory (91%). Among these genes, we showed that 5-FU increases the mRNA translation of HIVEP2, which encodes a transcription factor whose translation in normal condition is known to be inhibited by mir-155. In response to 5-FU, the expression of mir-155 decreases thus stimulating the translation of HIVEP2 mRNA. Interestingly, the 5-FU-induced increase in specific mRNA translation was associated with reduction of global protein synthesis. Altogether, these findings indicate that 5-FU promotes a translational reprogramming leading to the increased translation of a subset of mRNAs that involves at least for some of them, miRNA-dependent mechanisms. This study supports a still poorly evaluated role of translational control in drug response.
    Language English
    Publishing date 2017-07-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.17597
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Evidence for rRNA 2'-O-methylation plasticity: Control of intrinsic translational capabilities of human ribosomes.

    Erales, Jenny / Marchand, Virginie / Panthu, Baptiste / Gillot, Sandra / Belin, Stéphane / Ghayad, Sandra E / Garcia, Maxime / Laforêts, Florian / Marcel, Virginie / Baudin-Baillieu, Agnès / Bertin, Pierre / Couté, Yohann / Adrait, Annie / Meyer, Mélanie / Therizols, Gabriel / Yusupov, Marat / Namy, Olivier / Ohlmann, Théophile / Motorin, Yuri /
    Catez, Frédéric / Diaz, Jean-Jacques

    Proceedings of the National Academy of Sciences of the United States of America

    2017  Volume 114, Issue 49, Page(s) 12934–12939

    Abstract: Ribosomal RNAs (rRNAs) are main effectors of messenger RNA (mRNA) decoding, peptide-bond formation, and ribosome dynamics during translation. Ribose 2'-O-methylation (2'-O-Me) is the most abundant rRNA chemical modification, and displays a complex ... ...

    Abstract Ribosomal RNAs (rRNAs) are main effectors of messenger RNA (mRNA) decoding, peptide-bond formation, and ribosome dynamics during translation. Ribose 2'-O-methylation (2'-O-Me) is the most abundant rRNA chemical modification, and displays a complex pattern in rRNA. 2'-O-Me was shown to be essential for accurate and efficient protein synthesis in eukaryotic cells. However, whether rRNA 2'-O-Me is an adjustable feature of the human ribosome and a means of regulating ribosome function remains to be determined. Here we challenged rRNA 2'-O-Me globally by inhibiting the rRNA methyl-transferase fibrillarin in human cells. Using RiboMethSeq, a nonbiased quantitative mapping of 2'-O-Me, we identified a repertoire of 2'-O-Me sites subjected to variation and demonstrate that functional domains of ribosomes are targets of 2'-O-Me plasticity. Using the cricket paralysis virus internal ribosome entry site element, coupled to in vitro translation, we show that the intrinsic capability of ribosomes to translate mRNAs is modulated through a 2'-O-Me pattern and not by nonribosomal actors of the translational machinery. Our data establish rRNA 2'-O-Me plasticity as a mechanism providing functional specificity to human ribosomes.
    MeSH term(s) Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Gene Expression Regulation ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Methylation ; Protein Biosynthesis ; RNA, Ribosomal/metabolism
    Chemical Substances Chromosomal Proteins, Non-Histone ; RNA, Ribosomal ; fibrillarin
    Language English
    Publishing date 2017-11-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1707674114
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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