Author: "Emmanuelle Josselin" - Searchworks@Jio Institute Digital Library Search Results

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1. BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

Author: Violette Azzoni, Julien Wicinski, Manon Macario, Martin Castagné, Pascal Finetti, Katerina Ambrosova, Célia D. Rouault, Arnaud Sergé, Anne Farina, Emilie Agavnian, Sergiu Coslet, Emmanuelle Josselin, Arnaud Guille, José Adelaide, Emmanouil Zacharioudakis, Rémy Castellano, Francois Bertucci, Daniel Birnbaum, Raphael Rodriguez, Emmanuelle Charafe-Jauffret, and Christophe Ginestier
Subjects: Cytology, QH573-671
Abstract: Abstract Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.
Published: 2022
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2. Targeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity

Author: Eric Vivier, Daniel Olive, Remy Castellano, Els Verhoeyen, Pierre-Louis Bernard, Rebecca Delconte, Sonia Pastor, Vladimir Laletin, Cathy Costa Da Silva, Armelle Goubard, Emmanuelle Josselin, Adrien Krug, Julien Vernerey, Raynier Devillier, Nicholas D Huntington, Jacques Nunes, and Geoffrey Guittard
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2022
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3. A genome‐wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells

Author: Abir Arfaoui, Claire Rioualen, Violette Azzoni, Guillaume Pinna, Pascal Finetti, Julien Wicinski, Emmanuelle Josselin, Manon Macario, Rémy Castellano, Candi Léonard‐Stumpf, Anthony Bal, Abigaelle Gros, Sylvain Lossy, Maher Kharrat, Yves Collette, Francois Bertucci, Daniel Birnbaum, Hayet Douik, Ghislain Bidaut, Emmanuelle Charafe‐Jauffret, and Christophe Ginestier
Subjects: breast cancer, cancer stem cells, JQ1, RNAi screen, salinomycin, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Therapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSCs may represent a reservoir of therapeutic target to improve cancer treatment. Here, we carried out a genome‐wide RNA interference screen to identify genes that regulate breast CSCs‐fate (bCSC). Using an interactome/regulome analysis, we integrated screen results in a functional mapping of the CSC‐related processes. This network analysis uncovered potential therapeutic targets controlling bCSC‐fate. We tested a panel of 15 compounds targeting these regulators. We showed that mifepristone, salinomycin, and JQ1 represent the best anti‐bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/JQ1 association to deplete the bCSC population. Treatment of primary breast cancer xenografts with this combination reduced the tumor‐initiating cell population and limited metastatic development. The clinical relevance of our findings was reinforced by an association between the expression of the bCSC‐related networks and patient prognosis. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer.
Published: 2019
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4. Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Author: Fabienne Lamballe, Fahmida Ahmad, Yaron Vinik, Olivier Castellanet, Fabrice Daian, Anna‐Katharina Müller, Ulrike A. Köhler, Anne‐Laure Bailly, Emmanuelle Josselin, Rémy Castellano, Christelle Cayrou, Emmanuelle Charafe‐Jauffret, Gordon B. Mills, Vincent Géli, Jean‐Paul Borg, Sima Lev, and Flavio Maina
Subjects: BCL‐XL, cancer mouse model, drug resistance, MET, signaling reprogramming, triple‐negative breast cancer, Science
Abstract: Abstract Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.
Published: 2021
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5. The SCRIB Paralog LANO/LRRC1 Regulates Breast Cancer Stem Cell Fate through WNT/β-Catenin Signaling

Author: Leonor Lopez Almeida, Michael Sebbagh, François Bertucci, Pascal Finetti, Julien Wicinski, Sylvie Marchetto, Rémy Castellano, Emmanuelle Josselin, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Jean-Paul Borg, and Marie-Josée Santoni
Subjects: Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Summary: Tumor initiation, progression, and therapeutic resistance have been proposed to originate from a subset of tumor cells, cancer stem cells (CSCs). However, the current understanding of the mechanisms involved in their self-renewal and tumor initiation capacity remains limited. Here, we report that expression of LANO/LRRC1, the vertebrate paralog of SCRIB tumor suppressor, is associated with a stem cell signature in normal and tumoral mammary epithelia. Through in vitro and in vivo experiments including a Lano/Lrrc1 knockout mouse model, we demonstrate its involvement in the regulation of breast CSC (bCSC) fate. Mechanistically, we demonstrate that Lano/LRRC1-depleted cells secrete increased levels of WNT ligands, which act in a paracrine manner to positively deregulate the WNT/β-catenin pathway in bCSCs. In addition to describing the first function of LANO/LRRC1, our results suggest that its expression level could be used as a biomarker to stratify breast cancer patients who could benefit from WNT/β-catenin signaling inhibitors. : In this article, Santoni and colleagues report that expression of LANO/LRRC1, the paralog of SCRIB tumor suppressor, is associated with normal and tumoral mammary stem cell signature. Lano/LRRC1 represses expansion of cancer stem cell pool through inhibition of WNT ligand secretion and related WNT/β-catenin pathway activation. LANO/LRRC1 might have theranostic value to steer patient treatment by WNT/β-catenin signaling inhibitors. Keywords: breast cancer, stem cell, LANO/LRRC1, SCRIB, Wnt/β-catenin, tumor suppressor
Published: 2018
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6. A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer

Author: Joanie Del Bano, Rémy Florès-Florès, Emmanuelle Josselin, Armelle Goubard, Laetitia Ganier, Rémy Castellano, Patrick Chames, Daniel Baty, and Brigitte Kerfelec
Subjects: bispecific antibody (bsAb), natural killer cells, immunotherapy, triple negative breast cancer (TNBC), mesothelin (MSLN), multicellular tumor spheroid model (MCTS), Immunologic diseases. Allergy, RC581-607
Abstract: Triple negative breast cancers (TNBC) remain a major medical challenge due to poor prognosis and limited treatment options. Mesothelin is a glycosyl-phosphatidyl inositol-linked membrane protein with restricted normal expression and high level expression in a large proportion of TNBC, thus qualifying as an attractive target. Its overexpression in breast tumors has been recently correlated with a decreased disease-free survival and an increase of distant metastases. The objective of the study was to investigate the relevance of a bispecific antibody-based immunotherapy approach through mesothelin targeting and CD16 engagement using a Fab-like bispecific format (MesobsFab). Using two TNBC cell lines with different level of surface mesothelin and epithelial/mesenchymal phenotypes, we showed that, in vitro, MesobsFab promotes the recruitment and penetration of NK cells into tumor spheroids, induces potent dose-dependent cell-mediated cytotoxicity of mesothelin-positive tumor cells, cytokine secretion, and decreases cell invasiveness. MesobsFab was able to induce cytotoxicity in resting human peripheral blood mononuclear cells (PBMC), mainly through its NK cells-mediated antibody dependent cell cytotoxicity (ADCC) activity. In vivo, the anti-tumor effect of MesobsFab depends upon a threshold of MSLN density on target cells. Collectively our data support mesothelin as a relevant therapeutic target for the subset of TNBC that overexpresses mesothelin characterized by a low overall and disease-free survival as well as the potential of MesobsFab as antibody-based immunotherapeutics.
Published: 2019
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7. Vitamin D Controls Tumor Growth and CD8+ T Cell Infiltration in Breast Cancer

Author: Esma Karkeni, Stéphanie O. Morin, Berna Bou Tayeh, Armelle Goubard, Emmanuelle Josselin, Rémy Castellano, Cyril Fauriat, Geoffrey Guittard, Daniel Olive, and Jacques A. Nunès
Subjects: immunonutrition, vitamin D, breast cancer, CD8+ T cells, inflammation, Immunologic diseases. Allergy, RC581-607
Abstract: Women with low levels of vitamin D have a higher risk of developing breast cancer. Numerous studies associated the presence of a CD8+ T cell infiltration with a good prognosis. As vitamin D may play a key role in the modulation of the immune system, the objective of this work was to evaluate the impact of vitamin D on the breast cancer progression and mammary tumor microenvironment. We show that vitamin D decreases breast cancer tumor growth. Immunomonitoring of the different immune subsets in dissociated tumors revealed an increase in tumor infiltrating CD8+ T cells in the vitamin D-treated group. Interestingly, these CD8+ T cells exhibited a more active T cell (TEM/CM) phenotype. However, in high-fat diet conditions, we observed an opposite effect of vitamin D on breast cancer tumor growth, associated with a reduction of CD8+ T cell infiltration. Our data show that vitamin D is able to modulate breast cancer tumor growth and inflammation in the tumor microenvironment in vivo. Unexpectedly, this effect is reversed in high-fat diet conditions, revealing the importance of diet on tumor growth. We believe that supplementation with vitamin D can in certain conditions represent a new adjuvant in the treatment of breast cancers.
Published: 2019
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8. Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1) in breast cancer.

Author: Lynda Mezil, Carole Berruyer-Pouyet, Olivier Cabaud, Emmanuelle Josselin, Sébastien Combes, Jean-Michel Brunel, Patrice Viens, Yves Collette, Daniel Birnbaum, and Marc Lopez
Subjects: Medicine, Science
Abstract: BACKGROUND: Targeted therapies, associated with standard chemotherapies, have improved breast cancer care. However, primary and acquired resistances are frequently observed and the development of new concepts is needed. High-throughput approaches to identify new active and safe molecules with or without an "a priori" are currently developed. Also, repositioning already-approved drugs in cancer therapy is of growing interest. The thiomorpholine hydroxamate compound TMI-1 has been previously designed to inhibit metalloproteinase activity for the treatment of rheumatoid arthritis. We present here the repositioning of TMI-1 drug in breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of TMI-1 on luminal, basal and ERBB2-overexpressing breast tumor cell lines and on MMTV-ERBB2/neu tumor evolution. We measured the effects on i) cell survival, ii) cell cycle, iii) extrinsic and intrinsic apoptotic pathways, iv) association with doxorubicin, docetaxel and lapatinib, v) cancer stem cells compartment. In contrast with conventional cytotoxic drugs, TMI-1 was highly selective for tumor cells and cancer stem cells at submicromolar range. All non-malignant cells tested were resistant even at high concentration. TMI-1 was active on triple negative (TN) and ERBB2-overexpressing breast tumor cell lines, and was also highly efficient on human and murine "primary" ERBB2-overexpressing cells. Treatment of transgenic MMTV-ERBB2/neu mice with 100 mg/kg/day TMI-1 alone induced tumor apoptosis, inhibiting mammary gland tumor occurrence and development. No adverse effects were noticed during the treatment. This compound had a strong synergistic effect in association with docetaxel, doxorubicin and lapatinib. We showed that TMI-1 mediates its selective effects by caspase-dependent apoptosis. TMI-1 was efficient in 34/40 tumor cell lines of various origins (ED50: 0.6 µM to 12.5 µM). CONCLUSIONS/SIGNIFICANCE: This is the first demonstration of the tumor selective cytotoxic action of a thiomorpholin hydroxamate compound. TMI-1 is a novel repositionable drug not only for the treatment of adverse prognosis breast cancers but also for other neoplasms.
Published: 2012
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9. Correction: Effects of Deletion of Macrophage ABCA7 on Lipid Metabolism and the Development of Atherosclerosis in the Presence and Absence of ABCA1.

Author: Illiana Meurs, Laura Calpe-Berdiel, Kim L. L. Habets, Ying Zhao, Suzanne J. A. Korporaal, A. Mieke Mommaas, Emmanuelle Josselin, Reeni B. Hildebrand, Dan Ye, Ruud Out, Johan Kuiper, Theo J. C. Van Berkel, Giovanna Chimini, and Miranda Van Eck
Subjects: Medicine, Science
Published: 2012
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10. Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1.

Author: Illiana Meurs, Laura Calpe-Berdiel, Kim L L Habets, Ying Zhao, Suzanne J A Korporaal, A Mieke Mommaas, Emmanuelle Josselin, Reeni B Hildebrand, Dan Ye, Ruud Out, Johan Kuiper, Theo J C Van Berkel, Giovanna Chimini, and Miranda Van Eck
Subjects: Medicine, Science
Abstract: ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p
Published: 2012
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11. Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP.

Author: Wafa Frigui, Daria Bottai, Laleh Majlessi, Marc Monot, Emmanuelle Josselin, Priscille Brodin, Thierry Garnier, Brigitte Gicquel, Carlos Martin, Claude Leclerc, Stewart T Cole, and Roland Brosch
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Analysis of mycobacterial strains that have lost their ability to cause disease is a powerful approach to identify yet unknown virulence determinants and pathways involved in tuberculosis pathogenesis. Two of the most widely used attenuated strains in the history of tuberculosis research are Mycobacterium bovis BCG (BCG) and Mycobacterium tuberculosis H37Ra (H37Ra), which both lost their virulence during in vitro serial passage. Whereas the attenuation of BCG is due mainly to loss of the ESAT-6 secretion system, ESX-1, the reason why H37Ra is attenuated remained unknown. However, here we show that a point mutation (S219L) in the predicted DNA binding region of the regulator PhoP is involved in the attenuation of H37Ra via a mechanism that impacts on the secretion of the major T cell antigen ESAT-6. Only H37Ra "knock-ins" that carried an integrated cosmid with the wild-type phoP gene from M. tuberculosis H37Rv showed changes in colony morphology, increased virulence, ESAT-6 secretion, and induction of specific T cell responses, whereas other H37Ra constructs did not. This finding established a link between the PhoP regulator and ESAT-6 secretion that opens exciting new perspectives for elucidating virulence regulation in M. tuberculosis.
Published: 2008
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12. Supplementary Table 2 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 43K, Phenotype of BCLs after abexinostat treatment
Published: 2023
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13. Supplementary Figure Legend from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 86K, supplementary figure legend
Published: 2023
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14. Supplementary Figure 3 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 109K, Conventional molecular parameters do not predict drug-response to abexinostat
Published: 2023
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15. Supplementary Figure 8 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 35K, Expression level of Xist in patient-derived xenograft
Published: 2023
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16. Supplementary Figure 5 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 164K, Cell cycle progression was differentially altered by abexinostat according to drug-response profile
Published: 2023
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17. Supplementary Figure 4 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 123K, HDAC activity is impaired by treatment independently of drugresponse profiles
Published: 2023
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18. Data from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: Purpose: Cancer stem cells (CSC) are the tumorigenic cell population that has been shown to sustain tumor growth and to resist conventional therapies. The purpose of this study was to evaluate the potential of histone deacetylase inhibitors (HDACi) as anti-CSC therapies.Experimental Design: We evaluated the effect of the HDACi compound abexinostat on CSCs from 16 breast cancer cell lines (BCL) using ALDEFLUOR assay and tumorsphere formation. We performed gene expression profiling to identify biomarkers predicting drug response to abexinostat. Then, we used patient-derived xenograft (PDX) to confirm, in vivo, abexinostat treatment effect on breast CSCs according to the identified biomarkers.Results: We identified two drug-response profiles to abexinostat in BCLs. Abexinostat induced CSC differentiation in low-dose sensitive BCLs, whereas it did not have any effect on the CSC population from high-dose sensitive BCLs. Using gene expression profiling, we identified the long noncoding RNA Xist (X-inactive specific transcript) as a biomarker predicting BCL response to HDACi. We validated that low Xist expression predicts drug response in PDXs associated with a significant reduction of the breast CSC population.Conclusions: Our study opens promising perspectives for the use of HDACi as a differentiation therapy targeting the breast CSCs and identified a biomarker to select patients with breast cancer susceptible to responding to this treatment. Clin Cancer Res; 19(23); 6520–31. ©2013 AACR.
Published: 2023
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19. Supplementary Figure 7 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 126K, The effect of abexinostat on CSC is achieved through the specific inhibition of HDACs
Published: 2023
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20. Supplementary Table 3 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 54K, Karyotypes of BCLs
Published: 2023
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21. Supplementary Figure 1 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 166K, Identification of two drug-response groups using a Gaussian mixture model (GMM)
Published: 2023
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22. Supporting Information from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 68K, Supplementary materials and methods
Published: 2023
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23. Supplementary Table 1 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 44K, Clinical and pathological features of the breast cancer cell lines (BCLs)
Published: 2023
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24. Supplementary Figure 6 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 85K, Histone deacetylase inhibitors target the CSC population in lowdose sensitive BCLs
Published: 2023
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25. Supplementary Figure 2 from The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Christophe Ginestier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Yves Collette, François Bertucci, Stéphane Depil, Laurence Kraus-Berthier, Hélène Lelièvre, Emmanuelle Josselin, Pascal Finetti, Yves Toiron, Olivier Cabaud, Julien Wicinski, and Marion A. Salvador
Abstract: PDF file 192K, HDACi treatments define two drug-response profiles in BCLs
Published: 2023
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26. Supplementary Table 2 from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: PDF file - 56K, Table SII.CSC frequency in three independent PDXs (CRCM226 x, CRCM168 x, CRCM174 x).
Published: 2023
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27. Supplementary Table 1 from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: Table SI. Histoclinical and molecular parameters of the 74 primary tumors injected
Published: 2023
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28. Supplementary Figure Legends from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: PDF file - 87K
Published: 2023
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29. Supplementary Figures 1 - 14 from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: PDF file - 3065K, Figure S1. Average delay of growth of PDXs among passages (up to P5). Figure S2. DNA copy number variations found in the original primary tumors are well maintained in PDXs. Figure S3. Example of stromal dilution in parental primary tumor CRCM184 PT compared to paired CRCM 184 X. Figure S4. ALDEFLUOR phenotype of our 20 PDX models. Figure S5. Outgrowth kinetic of each sorted cell population isolated from three PDXs and injected in limited dilutions in fat pads of NSG mice. Figure S6. Univariate and multivariate analysis identified primary tumor engrafment as independent parameter associated with metastasis-free survival (MFS) in the series of 74 patients. Figure S7. Identification of parameters that predict successful engraftment. Figure S8. Global gene expression profiling of 53 PDXs. Figure S9. Supervised analyses of aCGH data comparing copy number variations in 17 paired primary tumors/PDXs. Figure S10. Representative network of genes isolated from the BCSC-GES and involved in DNA damage repair. Figure S11. Representative network of genes isolated from the BCSC-GES and involved in cell cycle control. Figure S12. The ?common? stem cell core transcriptional program (CE-4SC) is associated with clinical outcome. Figure S13. Functional validation of the CE-4SC in two different breast cancer cell lines (BCLs). Figure S14. Knock-down of genes from the CE-4SC affect tumorsphere-forming efficiency (SFE) in S68 BCL.
Published: 2023
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30. Supplementary Methods from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: PDF file - 97K
Published: 2023
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31. Supplementary Table 6 from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: Table SVI: Correlation between histoclinical and molecular parameters and our BCSC-GES in 2609 patients from public datasets
Published: 2023
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32. Supplementary Table 3 from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: Table SIII. Breast cancer stem cell gene expression signature (BCSC-GES)
Published: 2023
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33. Supplementary Table 4 from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: Table SIII. Breast cancer stem cell gene expression signature (BCSC-GES)
Published: 2023
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34. Supplementary Table 5 from ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Daniel Birnbaum, Patrice Viens, Max Chaffanet, Annick Harel-Bellan, Luc Xerri, Gilles Houvenaeghel, Eric Lambaudie, Aurélie Jalaguier, Guillaume Pinna, Jeanne Thomassin-Piana, Jocelyne Jacquemier, Florence Monville, Tien-Tuan Nguyen, José Adelaide, Emmanuelle Josselin, Pascal Finetti, Julien Wicinski, Olivier Cabaud, François Bertucci, Christophe Ginestier, and Emmanuelle Charafe-Jauffret
Abstract: Table SV. Public datasets description utilised for the BCSC-GES study
Published: 2023
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35. Induction of telomerase in p21-positive cells counteracts capillaries rarefaction in aging mice lung

Author: Larissa Lipskaia, Marielle Breau, Christelle Cayrou, Dmitri Churikov, Laura Braud, Charles Fouillade, Sandra Curras-Alonso, Serge Bauwens, Frederic Jourquin, Frederic Fiore, Rémy Castellano, Emmanuelle Josselin, Carlota Sánchez-Ferrer, Giovanna Giovinazzo, Eric Gilson, Ignacio Flores, Arturo Londono-Vallejo, Serge Adnot, Vincent Géli, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Abstract: Telomerase is required for long-term cell proliferation and linked to stem cells. This is evident in the lung where short telomeres are associated with lung dysfunction. We constructed a mouse model in which the telomerase (Tert) is expressed from the p21Cdkn1apromoter. We found that this peculiar Tert expression curb age-related emphysema and pulmonary perivascular fibrosis in old mice. In old mice lungs, such Tert expression preferentially occurs in endothelial cells where it reduces the number of senescent endothelial cells. Remarkably, we report that Tert counteracts the age-related decline in capillary density. This was associated with an increased number of Cd34+ cells identified as a subclass of capillary cells with proliferative capacity. Expression of catalytically inactiveTertneither prevents the decline of capillary density in old mice nor protects against age-related emphysema and fibrosis. These findings reveal that telomerase decreases age-decline of pulmonary functions by sustaining microvasculature regeneration and outgrowth.
Published: 2022
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36. Targeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity

Author: R. B. Delconte, Eric Vivier, Armelle Goubard, C. Costa Da Silva, A. Krug, Nicholas D. Huntington, Daniel Olive, Jacques A. Nunès, Raynier Devillier, Julien Vernerey, Els Verhoeyen, Sonia Pastor, Emmanuelle Josselin, P-L. Bernard, V. Laletin, Rémy Castellano, Geoffrey Guittard, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Memorial Sloan-Kettering Cancer Institute, Memorial Sloane Kettering Cancer Center [New York], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Innate Pharma, Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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), and DUMENIL, Anita
Subjects: Cancer Research, medicine.medical_treatment, Receptor expression, [SDV]Life Sciences [q-bio], Cell, Immunology, Suppressor of Cytokine Signaling Proteins, Mice, TIGIT, Neoplasms, medicine, Animals, Humans, Immunology and Allergy, CISH, Pharmacology, Natural Cytotoxicity Triggering Receptor 1, Chemistry, Immunotherapy, Immune checkpoint, Killer Cells, Natural, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cell killing, Cytokine, Oncology, Cancer research, Molecular Medicine
Abstract: BackgroundThe success and limitations of current immunotherapies have pushed research toward the development of alternative approaches and the possibility to manipulate other cytotoxic immune cells such as natural killer (NK) cells. Here, we targeted an intracellular inhibiting protein ‘cytokine inducible SH2-containing protein’ (CISH) in NK cells to evaluate the impact on their functions and antitumor properties.MethodsTo further understand CISH functions in NK cells, we developed a conditional Cish-deficient mouse model in NK cells (Cishfl/flNcr1Ki/+). NK cells cytokine expression, signaling and cytotoxicity has been evaluated in vitro. Using intravenous injection of B16F10 melanoma cell line and EO711 triple negative breast cancer cell line, metastasis evaluation was performed. Then, orthotopic implantation of breast tumors was performed and tumor growth was followed using bioluminescence. Infiltration and phenotype of NK cells in the tumor was evaluated. Finally, we targeted CISH in human NK-92 or primary NK cells, using a technology combining the CRISPR(i)-dCas9 tool with a new lentiviral pseudotype. We then tested human NK cells functions.ResultsIn Cishfl/flNcr1Ki/+ mice, we detected no developmental or homeostatic difference in NK cells. Global gene expression of Cishfl/flNcr1Ki/+ NK cells compared with Cish+/+Ncr1Ki/+ NK cells revealed upregulation of pathways and genes associated with NK cell cycling and activation. We show that CISH does not only regulate interleukin-15 (IL-15) signaling pathways but also natural cytotoxicity receptors (NCR) pathways, triggering CISH protein expression. Primed Cishfl/flNcr1Ki/+ NK cells display increased activation upon NCR stimulation. Cishfl/flNcr1Ki/+ NK cells display lower activation thresholds and Cishfl/flNcr1Ki/+ mice are more resistant to tumor metastasis and to primary breast cancer growth. CISH deletion favors NK cell accumulation to the primary tumor, optimizes NK cell killing properties and decreases TIGIT immune checkpoint receptor expression, limiting NK cell exhaustion. Finally, using CRISPRi, we then targeted CISH in human NK-92 or primary NK cells. In human NK cells, CISH deletion also favors NCR signaling and antitumor functions.ConclusionThis study represents a crucial step in the mechanistic understanding and safety of Cish targeting to unleash NK cell antitumor function in solid tumors. Our results validate CISH as an emerging therapeutic target to enhance NK cell immunotherapy.
Published: 2022
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37. Telomerase Prevents Emphysema in Old Mice by Sustaining Subpopulations of Endothelial and AT2 Cells

Author: Marielle Breau, Christelle Cayrou, Dmitri Churikov, Charles Fouillade, Sandra Curras-Alonso, Serge Bauwens, Frederic Jourquin, Laura Braud, Frederic Fiore, Rémy Castellano, Emmanuelle Josselin, Carlota Sánchez-Ferrer, Giovanna Giovinazzo, Eric Gilson, Ignacio Flores, Arturo Londono-Vallejo, Serge Adnot, Vincent Géli, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de neurosciences intégratives et cognitives (CNIC), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), 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 National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), and CAYROU, CHRISTELLE
Subjects: 0303 health sciences, telomere, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], senescence, aging, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], respiratory system, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], lung, stem cell, 03 medical and health sciences, 0302 clinical medicine, emphysema, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Telomerase, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Accumulation of senescent cells has been causally linked to the development of age-related pathologies. Here, we characterized a new mouse model (p21+/Tert) whose telomerase (TERT) is expressed from the p21 promoter that can be activated in response to telomere dysfunction. Lung parenchyma from p21+/Tert old mice accumulated fewer senescent cells with age and this correlated with a reduction in age-related alveolar space enlargement, a feature of pulmonary emphysema. This protection against emphysema depends on TERT catalytic activity and is associated with increased proliferation of pulmonary endothelial cells (EC) and capillary density. Single-cell RNA sequencing of lung cells revealed that TERT expression was associated with the enrichment of ECs expressing genes involved in vessel regeneration and in AT2 cells overexpressing S/G2M markers. These findings indicate that p21-promoter-dependent expression of catalytically active telomerase prevents emphysema by sustaining the proliferation of subclasses of EC and AT2 cells.
Published: 2022

38. Telomerase Prevents Emphysema in Old Mice by Sustaining Subpopulations of Endothelial and AT2 Cells

Author: Arturo Londoño-Vallejo, Serge Adnot, Frederic Jourquin, Giovanna Giovinazzo, Carlotta Sanchez-Ferrer, Christelle Cayrou, Ignacio Flores, Laura Braud, Marielle Breau, Sandra Curras-Alonso, Serge Bauwens, Emmanuelle Josselin, Frédéric Di Fiore, Eric Gilson, Charles Fouillade, Rémy Castellano, Vincent Géli, and Dmitri Churikov
Subjects: Telomerase, Lung, medicine.anatomical_structure, Chemistry, Pulmonary emphysema, Regeneration (biology), Parenchyma, medicine, RNA, respiratory system, Molecular biology, Gene, Epithelium
Abstract: Accumulation of senescent cells has been causally linked to the development of age-related pathologies. Here, we characterized a new mouse model (p21+/Tert) whose telomerase (TERT) is expressed from the p21 promoter that can be activated in response to telomere dysfunction. Lung parenchyma from p21+/Tert old mice accumulated fewer senescent cells with age and this correlated with a reduction in age-related alveolar space enlargement, a feature of pulmonary emphysema. This protection against emphysema depends on TERT catalytic activity and is associated with increased proliferation of pulmonary endothelial cells (EC) and capillary density. Single-cell RNA sequencing of lung cells revealed that TERT expression was associated with the enrichment of ECs expressing genes involved in vessel regeneration and in AT2 cells overexpressing S/G2M markers. These findings indicate that p21-promoter-dependent expression of catalytically active telomerase prevents emphysema by sustaining the proliferation of subclasses of EC and AT2 cells.
Published: 2021
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39. Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Author: Ulrike A. Köhler, Vincent Géli, Fahmida Ahmad, Fabrice Daian, Emmanuelle Josselin, Rémy Castellano, Sima Lev, Gordon B. Mills, Anna Katharina Müller, Christelle Cayrou, Olivier Castellanet, Jean-Paul Borg, Fabienne Lamballe, Yaron Vinik, Emmanuelle Charafe-Jauffret, Anne-Laure Bailly, Flavio Maina, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Weizmann Institute of Science [Rehovot, Israël], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Knight Cancer Institute, ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Poulain, Sébastien, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and CAYROU, CHRISTELLE
Subjects: BCL‐XL, General Chemical Engineering, [SDV]Life Sciences [q-bio], Druggability, General Physics and Astronomy, Medicine (miscellaneous), Bcl-xL, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Biochemistry, Genetics and Molecular Biology (miscellaneous), 03 medical and health sciences, Histone H3, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Downregulation and upregulation, medicine, General Materials Science, WEE1, lcsh:Science, Mitotic catastrophe, Triple-negative breast cancer, 030304 developmental biology, 0303 health sciences, drug resistance, Full Paper, biology, General Engineering, Full Papers, 021001 nanoscience & nanotechnology, medicine.disease, 0104 chemical sciences, 3. Good health, [SDV] Life Sciences [q-bio], Wee1, signaling reprogramming, triple‐negative breast cancer, Apoptosis, 030220 oncology & carcinogenesis, cancer mouse model, biology.protein, Cancer research, MET, lcsh:Q, 0210 nano-technology
Abstract: Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets., Triple‐negative breast cancer (TNBC) is highly aggressive and currently lacks effective treatment. This study reports the generation of a unique mouse model developing spontaneous, exclusive TNBC, recapitulating heterogeneity and primary resistance to treatments. Its clinical relevance is further strengthened by the identification of a potent drug combination for TNBC treatment, based on WEE1 and BCL‐XL targeting.
Published: 2020
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40. The SCRIB Paralog LANO/LRRC1 Regulates Breast Cancer Stem Cell Fate through WNT/β-Catenin Signaling

Author: Christophe Ginestier, Rémy Castellano, Leonor Lopez Almeida, Sylvie Marchetto, Marie-Josée Santoni, Emmanuelle Josselin, François Bertucci, Emmanuelle Charafe-Jauffret, Julien Wicinski, Jean-Paul Borg, Pascal Finetti, Michael Sebbagh, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Tumor initiation, Ligands, Biochemistry, law.invention, Mice, law, Neoplasm Metastasis, Wnt Signaling Pathway, lcsh:QH301-705.5, Wnt/β-catenin, lcsh:R5-920, Intracellular Signaling Peptides and Proteins, Wnt signaling pathway, SCRIB, 3. Good health, Gene Expression Regulation, Neoplastic, Knockout mouse, Neoplastic Stem Cells, Female, Stem cell, lcsh:Medicine (General), tumor suppressor, Down-Regulation, Breast Neoplasms, Biology, LANO/LRRC1, 03 medical and health sciences, Paracrine signalling, breast cancer, Cancer stem cell, Cell Line, Tumor, Report, Genetics, Animals, Humans, Cell Lineage, Sequence Homology, Amino Acid, Tumor Suppressor Proteins, Membrane Proteins, Epithelial Cells, Cell Biology, stem cell, 030104 developmental biology, lcsh:Biology (General), Cancer research, Suppressor, Carrier Proteins, Developmental Biology
Abstract: Summary Tumor initiation, progression, and therapeutic resistance have been proposed to originate from a subset of tumor cells, cancer stem cells (CSCs). However, the current understanding of the mechanisms involved in their self-renewal and tumor initiation capacity remains limited. Here, we report that expression of LANO/LRRC1, the vertebrate paralog of SCRIB tumor suppressor, is associated with a stem cell signature in normal and tumoral mammary epithelia. Through in vitro and in vivo experiments including a Lano/Lrrc1 knockout mouse model, we demonstrate its involvement in the regulation of breast CSC (bCSC) fate. Mechanistically, we demonstrate that Lano/LRRC1-depleted cells secrete increased levels of WNT ligands, which act in a paracrine manner to positively deregulate the WNT/β-catenin pathway in bCSCs. In addition to describing the first function of LANO/LRRC1, our results suggest that its expression level could be used as a biomarker to stratify breast cancer patients who could benefit from WNT/β-catenin signaling inhibitors., Highlights • Lano/LRRC1 expression level is associated with stem cell transcription signatures • Lano/LRRC1 is involved in the regulation of breast cancer stem cell fate • Lano/LRRC1 represses WNT ligand secretion, In this article, Santoni and colleagues report that expression of LANO/LRRC1, the paralog of SCRIB tumor suppressor, is associated with normal and tumoral mammary stem cell signature. Lano/LRRC1 represses expansion of cancer stem cell pool through inhibition of WNT ligand secretion and related WNT/β-catenin pathway activation. LANO/LRRC1 might have theranostic value to steer patient treatment by WNT/β-catenin signaling inhibitors.
Published: 2018
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41. Establishment of a mouse xenograft model of metastatic adrenocortical carcinoma

Author: Emmanuelle Josselin, Judith Favier, Rémy Castellano, Mabrouka Doghman-Bouguerra, Estelle Robidel, Enzo Lalli, Aurélie Morin, Carmen Ruggiero, Atze T. Das, MITOYAN, Louciné, Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours (UT)-EA3856, Sorbonne Université (SU), Inserm UMR970, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre de Recherche Cardiovasculaire de Lariboisiere, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AMC Liver Center, Academic Medical Center, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Laboratory of Experimental Virology - Department of Medical Microbiology [Amsterdam, The Netherlands], University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Center for Infection and Immunity Amsterdam - CINIMA [Amsterdam, The Netherlands], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université de Tours-EA3856, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Medical Microbiology and Infection Prevention
Subjects: green fluorescent protein, 0301 basic medicine, Pathology, medicine.medical_specialty, adrenal cortex, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Splenectomy, epithelial-mesenchymal transition, [SDV.CAN]Life Sciences [q-bio]/Cancer, cell lines, Disease, GFP, Steroidogenic Factor 1, Metastasis, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, adrenocortical carcinoma, cancer, Medicine, Neoplasm, Adrenocortical carcinoma, mouse models, Epithelial–mesenchymal transition, xenografts Abbreviations: ACC, business.industry, Adrenal cortex, EMT, Cancer, HES, medicine.disease, 3. Good health, hematoxylin-eosin-safran, [SDV] Life Sciences [q-bio], xenografts, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, SF-1, business, Research Paper
Abstract: International audience; Adrenocortical carcinoma is a rare neoplasm with a poor prognosis. Very important advances have been made in the identification of the genetic determinants of adrenocortical carcinoma pathogenesis but our understanding is still limited about the mechanisms that determine cancer spread and metastasis. One major problem hindering preclinical experimentation for new therapies for adrenocortical carcinoma is represented by the lack of suitable animal models for metastatic disease. With the aim to overcome these limitations, in this study we tested several protocols in order to establish a mouse xenograft model of metastatic adrenocortical carcinoma. The most efficient method, based upon intrasplenic injection followed by splenectomy, produced metastases with high efficiency, whose development could be followed over time by bioluminescence measurements. We expect that the availability of this model will greatly improve the possibilities for preclinical testing of new treatments for advanced-stage disease.
Published: 2017
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42. Correction to A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells

Author: Hariniaina Rampanarivo, Mickael Jean, Amélie Fouqué, Patrick Legembre, Mac Dinh Hung, Kenji F. Shoji, Yves Collette, Marine Malleter, Rémy Castellano, Emmanuelle Josselin, Pierre van de Weghe, Olivier Delalande, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structures et interactions moléculaires, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis (CRLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), and Bidaut, Ghislain
Subjects: Antitumor activity, Chemistry, In vivo, Covalent bond, Drug Discovery, Cancer research, Molecular Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Discovery and development of mTOR inhibitors, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Triple-negative breast cancer, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract: International audience
Published: 2019
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43. Vitamin D Controls Tumor Growth and CD8+ T Cell Infiltration in Breast Cancer

Author: Cyril Fauriat, Berna Bou Tayeh, Stéphanie O. Morin, Emmanuelle Josselin, Jacques A. Nunès, Esma Karkeni, Armelle Goubard, Daniel Olive, Geoffrey Guittard, Rémy Castellano, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (Inserm), Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université to CRCM, by the Fondation pour la Recherche Médicale (Equipe FRM DEQ20180339209). EK was supported by a post-doctoral fellowship from the Fondation pour la Recherche Médicale (SPF20160936267). GG was supported by a post-doctoral fellowship from the Fondation ARC pour la recherche sur le cancer, then the Janssen Horizon Fund. SOM and BBT were supported by a fellowship from Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Bidaut, Ghislain
Subjects: 0301 basic medicine, Vitamin, lcsh:Immunologic diseases. Allergy, T cell, [SDV]Life Sciences [q-bio], Immunology, Breast Neoplasms, vitamin D, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, CD8-Positive T-Lymphocytes, CD8+ T cells, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immune system, Breast cancer, Lymphocytes, Tumor-Infiltrating, breast cancer, Cell Line, Tumor, Vitamin D and neurology, Tumor Microenvironment, Immunology and Allergy, Medicine, Cytotoxic T cell, Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, immunonutrition, Cell Proliferation, Original Research, Mammary tumor, Tumor microenvironment, business.industry, medicine.disease, Prognosis, 3. Good health, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, chemistry, inflammation, Cancer research, Disease Progression, Female, business, lcsh:RC581-607, 030215 immunology
Abstract: International audience; Women with low levels of vitamin D have a higher risk of developing breast cancer. Numerous studies associated the presence of a CD8+ T cell infiltration with a good prognosis. As vitamin D may play a key role in the modulation of the immune system, the objective of this work was to evaluate the impact of vitamin D on the breast cancer progression and mammary tumor microenvironment. We show that vitamin D decreases breast cancer tumor growth. Immunomonitoring of the different immune subsets in dissociated tumors revealed an increase in tumor infiltrating CD8+ T cells in the vitamin D-treated group. Interestingly, these CD8+ T cells exhibited a more active T cell (TEM/CM) phenotype. However, in high-fat diet conditions, we observed an opposite effect of vitamin D on breast cancer tumor growth, associated with a reduction of CD8+ T cell infiltration. Our data show that vitamin D is able to modulate breast cancer tumor growth and inflammation in the tumor microenvironment in vivo. Unexpectedly, this effect is reversed in high-fat diet conditions, revealing the importance of diet on tumor growth. We believe that supplementation with vitamin D can in certain conditions represent a new adjuvant in the treatment of breast cancers.
Published: 2019
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44. Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer

Author: E. Agavnian-Couquiaud, Anthony Gonçalves, Patrice Viens, Pascal Finetti, G. Saviane, Daniel Olive, Christophe Ginestier, David Jérémie Birnbaum, M. M-Rabet, Anne Farina, Marc Lopez, Yves Collette, Emmanuelle Josselin, E Charafe-Jauffret, François Bertucci, Olivier Cabaud, Rémy Castellano, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), TrGET Platform, Cancérologie (Inserm U599/IPC), Université de la Méditerranée - Aix-Marseille 2-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Oncology, CA15-3, [SDV]Life Sciences [q-bio], Triple Negative Breast Neoplasms, Mice, 0302 clinical medicine, Aminobenzoates, Neoplasm Metastasis, Triple-negative breast cancer, Oligonucleotide Array Sequence Analysis, Antibodies, Monoclonal, Hematology, Middle Aged, Flow Cytometry, Prognosis, Immunohistochemistry, 3. Good health, 030220 oncology & carcinogenesis, nectin-4, Biomarker (medicine), biomarker, Female, Oligopeptides, TNBC, Adult, medicine.medical_specialty, CA 15-3, Antineoplastic Agents, Enzyme-Linked Immunosorbent Assay, [SDV.CAN]Life Sciences [q-bio]/Cancer, survival, 03 medical and health sciences, Breast cancer, breast cancer, In vivo, Internal medicine, medicine, Biomarkers, Tumor, Animals, Humans, business.industry, Cancer, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, ADC targeting, business, Cell Adhesion Molecules
Abstract: International audience; Background: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular sub-types, they have no identified specific target and chemotherapy remains the only available systemic treatment. The adhesion molecule nectin-4 represents a new potential therapeutic target in different cancer models. Here, we have tested the prognos-tic value of nectin-4 expression and assessed the therapeutic efficiency of an anti-nectin 4 antibody drug conjugate (ADC) on localised and metastatic TNBC in vitro and in vivo. Materials and methods: We analysed nectin-4/PVRL4 mRNA expression in 5673 invasive breast cancers and searched for correlations with clinicopathological features including metastasis-free survival (MFS). Immunohistochemistry was carried out in 61 TNBCs and in samples of primary TNBC Patient-Derived Xenografts (PDXs). An anti-nectin-4 antibody eligible for ADC was produced and tested in vitro and in vivo in localised and metastatic TNBC PDXs. Results: High nectin-4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal sub-types. High PVRL4 mRNA expression showed independent negative prognostic value for MFS in multivariate analysis in TNBCs. Nectin-4 protein expression was not detected in adult healthy tissues including mammary tissue. Membranous protein expression was found in 62% of TNBCs, with strong correlation with mRNA expression. We developed an ADC (N41mab-vcMMAE) comprising a human anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalisation as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, this ADC induced rapid, complete and durable responses on nectin-4-positive xenograft TNBC samples including primary tumours, metastatic lesions, and local relapses; efficiency was dependent on both the dose and the nectin-4 tumour expression level. Conclusion: Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC.
Published: 2017
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45. PRICKLE1 contributes to cancer cell dissemination through its interaction with mTORC2

Author: Pascal Finetti, Rémy Castellano, Jean-Paul Borg, Emmanuelle Josselin, François Bertucci, Avais M. Daulat, Stéphane Audebert, Daniel Birnbaum, Stephane Angers, Arnauld Sergé, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada, 9Department of Biochemistry, Faculty of Medicine, University of Toronto, This work was funded by La Ligue Nationale Contre le Cancer (Label Ligue JPB and DB, and post-doctoral fellowship to AMD), Fondation de France (post-doctoral fellowship to AMD), Fondation ARC pour la Recherche sur le Cancer (grant to JPB and AS), and SIRIC (INCa-DGOS-Inserm 6038, fellowship to AMD). The Marseille Proteomics (IBiSA) and TrGET platforms are supported by Institut Paoli-Calmettes (IPC) and Canceropôle PACA., Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and BORG, Jean-Paul
Subjects: 0301 basic medicine, MINK1, mTORC2, Cell Movement, Protein Interaction Mapping, Neoplasm Metastasis, Phosphorylation, Genes, Dominant, Kinase, TOR Serine-Threonine Kinases, cancer cell migration, LIM Domain Proteins, Prognosis, 3. Good health, Cell biology, Up-Regulation, Female, Protein Binding, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mechanistic Target of Rapamycin Complex 2, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Protein Serine-Threonine Kinases, General Biochemistry, Genetics and Molecular Biology, Focal adhesion, 03 medical and health sciences, Downregulation and upregulation, Protein Domains, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Humans, Molecular Biology, Protein kinase B, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, Focal Adhesions, PRICKLE1, Cell growth, Tumor Suppressor Proteins, Cell Biology, 030104 developmental biology, Rapamycin-Insensitive Companion of mTOR Protein, Multiprotein Complexes, Cancer cell, Cancer research, Carrier Proteins, Proto-Oncogene Proteins c-akt, Developmental Biology
Abstract: International audience; Components of the evolutionarily conserved developmental planar cell polarity (PCP) pathway were recently described to play a prominent role in cancer cell dissemination. However, the molecular mechanisms by which PCP molecules drive the spread of cancer cells remain largely unknown. PRICKLE1 encodes a PCP protein bound to the promigratory serine/threonine kinase MINK1. We identify RICTOR, a member of the mTORC2 complex, as a PRICKLE1-binding partner and show that the integrity of the PRICKLE1-MINK1-RICTOR complex is required for activation of AKT, regulation of focal adhesions, and cancer cell migration. Disruption of the PRICKLE1-RICTOR interaction results in a strong impairment of breast cancer cell dissemination in xenograft assays. Finally, we show that upregulation of PRICKLE1 in basal breast cancers, a subtype characterized by high metastatic potential, is associated with poor metastasis-free survival.
Published: 2016
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46. A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells

Author: Yves Collette, Kenji F. Shoji, Olivier Delalande, Rémy Castellano, Mac Dinh Hung, Patrick Legembre, Marine Malleter, Mickael Jean, Emmanuelle Josselin, Pierre van de Weghe, Hariniaina Rampanarivo, Amélie Fouqué, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Oncogenesis Stress Signaling (OSS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Institut National Du Cancer, Ministère de l'Enseignement Supérieur et de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Comité du Morbihan, Ligue Nationale Contre le Cancer, Comité de Maine-et-Loire, Ligue Nationale Contre le Cancer, Comité des Côtes-d'Armor, Ligue Nationale Contre le Cancer, Comité du Finistère, Ligue Nationale Contre le Cancer, Comité d’Ille-et-Vilaine, Ligue Nationale Contre le Cancer, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)
Subjects: Models, Molecular, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Breast Neoplasms, Metastasis, Mice, Structure-Activity Relationship, Mice, Inbred NOD, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Kinome, Benzopyrans, Kinase activity, Phosphorylation, PI3K/AKT/mTOR pathway, Triple-negative breast cancer, Phosphoinositide-3 Kinase Inhibitors, Kinase, Chemistry, TOR Serine-Threonine Kinases, RPTOR, medicine.disease, Molecular biology, 3. Good health, Oncogene Protein v-akt, Cancer cell, Cancer research, Molecular Medicine, Female, Drug Screening Assays, Antitumor, Signal Transduction
Abstract: International audience; Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology
Published: 2015
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47. Nectin-4 mutations causing ectodermal dysplasia with syndactyly perturb the rac1 pathway and the kinetics of adherens junction formation

Author: Massimo Teson, Konstantinos Tsiakas, Francesco Brancati, Marc Lopez, Bruno Dallapiccola, Gianluca Cestra, Giovanna Zambruno, Emmanuelle Josselin, Giuseppe Novelli, Paola Fortugno, René Santer, Daniele Castiglia, Ingo Kurth, and Emanuele Agolini
Subjects: rac1 GTP-Binding Protein, Ectodermal dysplasia, Cells, Nectins, RAC1, Dermatology, Biology, Compound heterozygosity, Biochemistry, Adherens junction, Dogs, Nectin, Ectodermal Dysplasia, medicine, Cell Adhesion, Missense mutation, Animals, Humans, Molecular Biology, Cells, Cultured, Cell Aggregation, Genetics, Cultured, Cadherin, Adherens Junctions, Cell Adhesion Molecules, Kinetics, Signal Transduction, Syndactyly, Mutation, 2708, Cell Biology, medicine.disease, Cell biology, Settore MED/03 - Genetica Medica, Ectopic expression
Abstract: Defective nectin-1 and -4 have been implicated in ectodermal dysplasia (ED) syndromes with variably associated features including orofacial and limb defects. In particular, nectin-1 mutations cause cleft lip/palate ED (CLPED1; OMIM#225060), whereas defective nectin-4 is associated with ED-syndactyly syndrome (EDSS1; OMIM#613573). Although the broad phenotypic overlap suggests a common mode of action of nectin-1 and -4, little is known about the pathogenic mechanisms involved. We report the identification of, to our knowledge, a previously undescribed nectin-4 homozygous p.Val242Met missense mutation in a patient with EDSS1. We used patient skin biopsy and primary keratinocytes, as well as nectin-4 ectopic expression in epithelial cell lines, to characterize functional consequences of p.Val242Met and p.Thr185Met mutations, the latter previously identified in compound heterozygosity with a truncating mutation. We show that nectin-4-altered expression perturbs nectin-1 clustering at keratinocyte contact sites and delays, but does not impede cell–cell aggregation and cadherin recruitment at adherens junctions (AJs). Moreover, trans-interaction of nectin-1 and -4 induces the activation of Rac1, a member of the Rho family of small GTPases, and regulates E-cadherin-mediated cell–cell adhesion. These data outline a synergistic action of nectin-1 and -4 in the early steps of AJ formation and implicate this interaction in modulating the Rac1 signaling pathway.
Published: 2014

48. The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Author: Stéphane Depil, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Olivier Cabaud, Christophe Ginestier, Laurence Kraus-Berthier, Marion A. Salvador, Hélène Lelièvre, François Bertucci, Yves Collette, Emmanuelle Josselin, Julien Wicinski, Pascal Finetti, Yves Toiron, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'études et de recherches sur la qualité des aliments et sur les procédés agroalimentaires, Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Oncol Res & Dev Unit, Institut de Recherches Servier, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Cancer Research, Abexinostat, Gene Expression, Mice, SCID, Bioinformatics, Hydroxamic Acids, chemistry.chemical_compound, Mice, 0302 clinical medicine, Differentiation therapy, Mice, Inbred NOD, 0303 health sciences, education.field_of_study, Histone deacetylase inhibitor, Cell Cycle, Cell Differentiation, 3. Good health, Tumor Burden, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Female, RNA, Long Noncoding, medicine.drug_class, Population, Antineoplastic Agents, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Inhibitory Concentration 50, Breast cancer, Cancer stem cell, Cell Line, Tumor, medicine, Biomarkers, Tumor, Animals, Humans, education, 030304 developmental biology, Benzofurans, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Histone Deacetylase Inhibitors, chemistry, Drug Resistance, Neoplasm, Cancer research, XIST
Abstract: Purpose: Cancer stem cells (CSC) are the tumorigenic cell population that has been shown to sustain tumor growth and to resist conventional therapies. The purpose of this study was to evaluate the potential of histone deacetylase inhibitors (HDACi) as anti-CSC therapies. Experimental Design: We evaluated the effect of the HDACi compound abexinostat on CSCs from 16 breast cancer cell lines (BCL) using ALDEFLUOR assay and tumorsphere formation. We performed gene expression profiling to identify biomarkers predicting drug response to abexinostat. Then, we used patient-derived xenograft (PDX) to confirm, in vivo, abexinostat treatment effect on breast CSCs according to the identified biomarkers. Results: We identified two drug-response profiles to abexinostat in BCLs. Abexinostat induced CSC differentiation in low-dose sensitive BCLs, whereas it did not have any effect on the CSC population from high-dose sensitive BCLs. Using gene expression profiling, we identified the long noncoding RNA Xist (X-inactive specific transcript) as a biomarker predicting BCL response to HDACi. We validated that low Xist expression predicts drug response in PDXs associated with a significant reduction of the breast CSC population. Conclusions: Our study opens promising perspectives for the use of HDACi as a differentiation therapy targeting the breast CSCs and identified a biomarker to select patients with breast cancer susceptible to responding to this treatment. Clin Cancer Res; 19(23); 6520–31. ©2013 AACR.
Published: 2013
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49. ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Author: Emmanuelle Charafe-Jauffret, Luc Xerri, Jocelyne Jacquemier, Pascal Finetti, Eric Lambaudie, Annick Harel-Bellan, Emmanuelle Josselin, Patrice Viens, Daniel Birnbaum, José Adélaïde, Aurélie Jalaguier, Julien Wicinski, Jeanne Thomassin-Piana, François Bertucci, Max Chaffanet, Florence Monville, Christophe Ginestier, Gilles Houvenaeghel, Guillaume Pinna, Olivier Cabaud, Tien-Tuan N'guyen, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Langevin - Ondes et Images (UMR7587) (IL), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cancérologie (Inserm U599/IPC), Université de la Méditerranée - Aix-Marseille 2-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biopathologie, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Chirurgicale, Département de chirurgie Paoli Calmette (Paoli Calmette), Département de Biopathologie, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire Epigénétique et Cancer (LEC), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, Population, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Transfection, Aldehyde Dehydrogenase 1 Family, 03 medical and health sciences, Mice, 0302 clinical medicine, Breast cancer, Cancer stem cell, Mice, Inbred NOD, medicine, Biomarkers, Tumor, Animals, Humans, Prospective Studies, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, Gene Expression Profiling, Cancer, Nucleic Acid Hybridization, Retinal Dehydrogenase, Cell Differentiation, medicine.disease, Prognosis, Embryonic stem cell, Neural stem cell, 3. Good health, Isoenzymes, Haematopoiesis, Oncology, 030220 oncology & carcinogenesis, Immunology, Cancer research, Neoplastic Stem Cells, Heterografts, Female, Stem cell
Abstract: Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor–derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer. Cancer Res; 73(24); 7290–300. ©2013 AACR.
Published: 2013
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50. Effects of Deletion of Macrophage ABCA7 on Lipid Metabolism and the Development of Atherosclerosis in the Presence and Absence of ABCA1

Author: Theo J.C. Van Berkel, Reeni B. Hildebrand, Ruud Out, Dan Ye, Ying Zhao, Illiana Meurs, A. Mieke Mommaas, Johan Kuiper, Laura Calpe-Berdiel, Emmanuelle Josselin, Suzanne J.A. Korporaal, Kim L. L. Habets, Miranda Van Eck, Giovanna Chimini, Division of Biopharmaceutics, Universiteit Leiden, Leiden University Medical Center (LUMC), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Universiteit Leiden [Leiden]
Subjects: Male, Anatomy and Physiology, lcsh:Medicine, 030204 cardiovascular system & hematology, Cardiovascular, Biochemistry, Gene Knockout Techniques, Mice, 0302 clinical medicine, Molecular Cell Biology, Macrophage, lcsh:Science, Phospholipids, Foam cell, 0303 health sciences, Multidisciplinary, Animal Models, Lipids, 3. Good health, Up-Regulation, medicine.anatomical_structure, Cholesterol, Erythropoiesis, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Cellular Types, Research Article, ATP Binding Cassette Transporter 1, medicine.medical_specialty, Bone marrow transplantation, T cell, Lipoproteins, Spleen, Biology, 03 medical and health sciences, Model Organisms, Internal medicine, medicine, Animals, 030304 developmental biology, Macrophages, lcsh:R, Proteins, Lipid metabolism, Lipid Metabolism, Atherosclerosis, Transplantation, Endocrinology, Gene Expression Regulation, Receptors, LDL, Immunology, lcsh:Q, ATP-Binding Cassette Transporters, Bone marrow, Gene expression, Foam Cells
Abstract: International audience; ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p
Published: 2012
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