Investigation préclinique

Publications

Année de publication : 2020

Coussy F, El-Botty R, Château-Joubert S, Dahmani A, Montaudon E, Leboucher S,Morisset L, Painsec P, Sourd L, Huguet L, Nemati F, Servely JL, Larcher T, Vacher S, Briaux A, Reyes C, La Rosa P, Lucotte G, Popova T, Foidart P, Sounni NE, Noel A, Decaudin D, Fuhrmann L, Salomon A, Reyal F, Mueller C, Ter Brugge P, Jonkers J, Poupon MF, Stern MH, Bièche I, Pommier Y, Marangoni E. (2020 Feb 19)

BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

Science Translational MedicineScience Translational Medicine : DOI : 10.1126/scitranslmed.aax2625 En savoir plus
Résumé

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Sunil Pancholi, Mariana Ferreira Leal, Ricardo Ribas, Nikiana Simigdala, Eugene Schuster, Sophie Chateau-Joubert, Lila Zabaglo, Margaret Hills, Andrew Dodson, Qiong Gao, Stephen R Johnston, Mitch Dowsett, Sabina C Cosulich, Elisabetta Marangoni, Lesley-Ann Martin (2020 Feb 2)

Correction to: Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.

Breast cancer research : BCR : 14 : DOI : 10.1186/s13058-020-1254-5 En savoir plus
Résumé

After publication of the original article [1], we were notified that an author’s surname has been erroneously spelled. Elisabetta Maragoni’s family name should be replaced with Marangoni.

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Anne-Sophie Hamy, Lisa Derosa, Constance Valdelièvre, Satoru Yonekura, Paule Opolon, Maël Priour, Julien Guerin, Jean-Yves Pierga, Bernard Asselain, Diane De Croze, Alice Pinheiro, Marick Lae, Laure-Sophie Talagrand, Enora Laas, Lauren Darrigues, Beatriz Grandal, Elisabetta Marangoni, Elodie Montaudon, Guido Kroemer, Laurence Zitvogel, Fabien Reyal (2020 Feb 1)

Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer.

Oncoimmunology : 1677427 : DOI : 10.1080/2162402X.2019.1677427 En savoir plus
Résumé

Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2 BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in -positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.

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Coussy F, Lavigne M, de Koning L, Botty RE, Nemati F, Naguez A, Bataillon G, Ouine B, Dahmani A, Montaudon E, Painsec P, Chateau-Joubert S, Laetitia F, Larcher T, Vacher S, Chemlali W, Briaux A, Melaabi S, Salomon AV, Guinebretiere JM, Bieche I, Marangoni E (2020 Jan 1)

Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts

TheranosticsTheranostics En savoir plus
Résumé

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Année de publication : 2019

Marina Bacci, Nicla Lorito, Luigi Ippolito, Matteo Ramazzotti, Simone Luti, Simone Romagnoli, Matteo Parri, Francesca Bianchini, Federica Cappellesso, Federico Virga, Qiong Gao, Bruno M Simões, Elisabetta Marangoni, Lesley-Ann Martin, Giuseppina Comito, Manuela Ferracin, Elisa Giannoni, Massimiliano Mazzone, Paola Chiarugi, Andrea Morandi (2019 Jul 4)

Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer.

Cell reports : 104-118.e8 : DOI : S2211-1247(19)30768-5 En savoir plus
Résumé

Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER) breast cancers. Despite its efficacy, ∼40% of women relapse with ET-resistant (ETR) disease. A global transcription analysis in ETR cells reveals a downregulation of the neutral and basic amino acid transporter SLC6A14 governed by enhanced miR-23b-3p expression, resulting in impaired amino acid metabolism. This altered amino acid metabolism in ETR cells is supported by the activation of autophagy and the enhanced import of acidic amino acids (aspartate and glutamate) mediated by the SLC1A2 transporter. The clinical significance of these findings is validated by multiple orthogonal approaches in a large cohort of ET-treated patients, in patient-derived xenografts, and in in vivo experiments. Targeting these amino acid metabolic dependencies resensitizes ETR cells to therapy and impairs the aggressive features of ETR cells, offering predictive biomarkers and potential targetable pathways to be exploited to combat or delay ETR in ER breast cancers.

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Coralie Poulard, Julien Jacquemetton, Olivier Trédan, Pascale A Cohen, Julie Vendrell, Sandra E Ghayad, Isabelle Treilleux, Elisabetta Marangoni, Muriel Le Romancer (2019 Jun 15)

Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer.

International journal of molecular sciences : DOI : E2773 En savoir plus
Résumé

Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα-Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.

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Mathilde Vinet, Samyuktha Suresh, Virginie Maire, Clarisse Monchecourt, Fariba Némati, Laetitia Lesage, Fabienne Pierre, Mengliang Ye, Auriane Lescure, Amélie Brisson, Didier Meseure, André Nicolas, Guillem Rigaill, Elisabetta Marangoni, Elaine Del Nery, Sergio Roman-Roman, Thierry Dubois (2019 Apr 9)

Protein arginine methyltransferase 5: A novel therapeutic target for triple-negative breast cancers.

Cancer medicine : 2414-2428 : DOI : 10.1002/cam4.2114 En savoir plus
Résumé

TNBC is a highly heterogeneous and aggressive breast cancer subtype associated with high relapse rates, and for which no targeted therapy yet exists. Protein arginine methyltransferase 5 (PRMT5), an enzyme which catalyzes the methylation of arginines on histone and non-histone proteins, has recently emerged as a putative target for cancer therapy. Potent and specific PRMT5 inhibitors have been developed, but the therapeutic efficacy of PRMT5 targeting in TNBC has not yet been demonstrated. Here, we examine the expression of PRMT5 in a human breast cancer cohort obtained from the Institut Curie, and evaluate the therapeutic potential of pharmacological inhibition of PRMT5 in TNBC. We find that PRMT5 mRNA and protein are expressed at comparable levels in TNBC, luminal breast tumors, and healthy mammary tissues. However, immunohistochemistry analyses reveal that PRMT5 is differentially localized in TNBC compared to other breast cancer subtypes and to normal breast tissues. PRMT5 is heterogeneously expressed in TNBC and high PRMT5 expression correlates with poor prognosis within this breast cancer subtype. Using the small-molecule inhibitor EPZ015666, we show that PRMT5 inhibition impairs cell proliferation in a subset of TNBC cell lines. PRMT5 inhibition triggers apoptosis, regulates cell cycle progression and decreases mammosphere formation. Furthermore, EPZ015666 administration to a patient-derived xenograft model of TNBC significantly deters tumor progression. Finally, we reveal potentiation between EGFR and PRMT5 targeting, suggestive of a beneficial combination therapy. Our findings highlight a distinctive subcellular localization of PRMT5 in TNBC, and uphold PRMT5 targeting, alone or in combination, as a relevant treatment strategy for a subset of TNBC.

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F Coussy, L de Koning, M Lavigne, V Bernard, B Ouine, A Boulai, R El Botty, A Dahmani, E Montaudon, F Assayag, L Morisset, L Huguet, L Sourd, P Painsec, C Callens, S Chateau-Joubert, J-L Servely, T Larcher, C Reyes, E Girard, G Pierron, C Laurent, S Vacher, S Baulande, S Melaabi, A Vincent Salomon, D Gentien, V Dieras, I Bieche, E Marangoni (2019 Mar 13)

A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer.

International journal of cancer : DOI : 10.1002/ijc.32266 En savoir plus
Résumé

Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-Derived Xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n=61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of SMGs (Significantly Mutated Gene) and SCNAs (Somatic Copy Number Alteration) in PDX and TCGA TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes.TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research. KEYS WORD: Triple-negative breast cancer, targeted therapies, patient-derived xenograft (PDX), integrated genomic analysis. This article is protected by copyright. All rights reserved.

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Ali Choucair, Thuy Ha Pham, Soleilmane Omarjee, Julien Jacquemetton, Loay Kassem, Olivier Trédan, Juliette Rambaud, Elisabetta Marangoni, Laura Corbo, Isabelle Treilleux, Muriel Le Romancer (2019 Jan 30)

The arginine methyltransferase PRMT1 regulates IGF-1 signaling in breast cancer.

Oncogene : 4015-4027 : DOI : 10.1038/s41388-019-0694-9 En savoir plus
Résumé

Aside from its well-known nuclear routes of signaling, estrogen also mediates its effects through cytoplasmic signaling. Estrogen signaling involves numerous posttranslational modifications of its receptor ERα, the best known being phosphorylation. Our research group previously showed that upon estrogen stimulation, ERα is methylated on residue R260 and forms the mERα/Src/PI3K complex, central to the rapid transduction of nongenomic estrogen signals. Regulation of ERα signaling via its phosphorylation by growth factors is well recognized, and we wondered whether they could also trigger ERα methylation (mERα). Here, we found that IGF-1 treatment of MCF-7 cells induced rapid ERα methylation by the arginine methyltransferase PRMT1 and triggered the binding of mERα to IGF-1R. Mechanistically, we showed that PRMT1 bound constitutively to IGF-1R and that PRMT1 became activated upon IGF-1 stimulation. Moreover, we found that expression or pharmacological inhibition of PRMT1 impaired mERα and IGF-1 signaling. Our findings were substantiated in a cohort of breast tumors in which IGF-1R expression was positively correlated with ERα/Src and ERα/PI3K expression, hallmarks of nongenomic estrogen signaling, reinforcing the link between IGF-1R and mERα. Altogether, these results provide a new insight into ERα and IGF-1R interference, and open novel perspectives for combining endocrine therapies with PRMT1 inhibitors in ERα-positive tumors.

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Année de publication : 2018

Pierre Foidart, Cassandre Yip, Jean Radermacher, Silvia Blacher, Mehdi Lienard, Laetitia Montero-Ruiz, Erik Maquoi, Elodie Montaudon, Sophie Château-Joubert, Joëlle Collignon, Michel Coibion, Véronique Jossa, Elisabetta Marangoni, Agnès Noël, Nor Eddine Sounni, Guy Jerusalem (2018 Dec 4)

Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy.

Clinical cancer research : an official journal of the American Association for Cancer Research : 1838-1850 : DOI : 10.1158/1078-0432.CCR-18-1880 En savoir plus
Résumé

Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB). IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in 2D and 3D proliferation assays and using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib + palbociclib) treatments.

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Paula Azorin, Florian Bonin, Ahmad Moukachar, Aurélie Ponceau, Sophie Vacher, Ivan Bièche, Elisabetta Marangoni, Laetitia Fuhrmann, Anne Vincent-Salomon, Rosette Lidereau, Keltouma Driouch (2018 Nov 28)

Distinct expression profiles and functions of Kindlins in breast cancer.

Journal of experimental & clinical cancer research : CR : 281 : DOI : 10.1186/s13046-018-0955-4 En savoir plus
Résumé

Kindlin-1, - 2, and - 3 are the three members of the Kindlin family. They are best known as regulators of integrin functions, contributing to fundamental biological processes such as cell survival, adhesion and migration. Their deregulation leads to diverse pathologies including a broad range of cancers in which both, tumor-promoting and tumor-inhibiting functions have been described.

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Alexandra Ruthenbeck, Elisa Marangoni, Björn-Ph Diercks, Aileen Krüger, Alexander Froese, Nadja I Bork, Viacheslav O Nikolaev, Andreas H Guse, Chris Meier (2018 Nov 16)

Membrane-Permeable Octanoyloxybenzyl-Masked cNMPs As Novel Tools for Non-Invasive Cell Assays.

Molecules (Basel, Switzerland) : DOI : E2960 En savoir plus
Résumé

Adenine nucleotide (AN) 2nd messengers, such as 3′,5′-cyclic adenosine monophosphate (cAMP), are central elements of intracellular signaling, but many details of their underlying processes remain elusive. Like all nucleotides, cyclic nucleotide monophosphates (cNMPs) are net-negatively charged at physiologic pH which limits their applicability in cell-based settings. Thus, many cellular assays rely on sophisticated techniques like microinjection or electroporation. This setup is not feasible for medium- to high-throughput formats, and the mechanic stress that cells are exposed to raises the probability of interfering artefacts or false-positives. Here, we present a short and flexible chemical route yielding membrane-permeable, bio-reversibly masked cNMPs for which we employed the octanoyloxybenzyl (OB) group. We further show hydrolysis studies on chemical stability and enzymatic activation, and present results of real-time assays, where we used cAMP and Ca live cell imaging to demonstrate high permeability and prompt intracellular conversion of some selected masked cNMPs. Based on these results, our novel OB-masked cNMPs constitute valuable precursor-tools for non-invasive studies on intracellular signaling.

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Philippe De La Rochere, Silvia Guil-Luna, Didier Decaudin, Georges Azar, Sukhvinder S Sidhu, Eliane Piaggio (2018 Aug 6)

Humanized Mice for the Study of Immuno-Oncology.

Trends in immunology : 748-763 : DOI : S1471-4906(18)30125-X En savoir plus
Résumé

Immunotherapy is revolutionizing cancer treatment; however, complete responses are achieved in only a small fraction of patients and tumor types. Thus, there is an urgent need for predictive preclinical models to drive rational immunotherapeutic drug development, treatment combinations, and to minimize failures in clinical trials. Humanized mouse models (HIS) have been developed to study and modulate the interactions between immune components and tumors of human origin. In this review, we discuss recent advances in the ‘humanization’ of mouse models to improve the quality of human immune cell reconstitution. We also highlight new insights into the basic mechanisms, and provide a preclinical evaluation of onco-immunotherapies, as well as the limitations thereof, which constitute drivers for the improvement of the models to increase their translational power.

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Rania El Botty, Florence Coussy, Rana Hatem, Franck Assayag, Sophie Chateau-Joubert, Jean-Luc Servely, Sophie Leboucher, Charles Fouillade, Sophie Vacher, Bérengère Ouine, Aurélie Cartier, Leanne de Koning, Paul Cottu, Ivan Bièche, Elisabetta Marangoni (2018 Jul 25)

Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition.

Oncotarget : 29587-29600 : DOI : 10.18632/oncotarget.25640 En savoir plus
Résumé

Breast cancer is a complex disease in which each patient could present several genetic alterations that are therapeutically relevant in cancers. Here we explored the therapeutic benefit of combining PARP and mTOR inhibitors in a context of DNA repair deficiency and PI3K pathway activation. The combination of everolimus and olaparib was tested in BRCA2-mutated patient-derived xenografts (PDX) carrying alterations in the PI3K/AKT/mTOR pathway. An RPPA analysis of different signalling pathways was performed in untreated and treated xenografts. Everolimus and olaparib showed marked anti-tumor activities in the monotherapy setting and high efficacy when given in combination with 100% of mice showing tumor regressions. The fraction of P-H2AX positive cells was increased in both monotherapy arms and strongly increased in the combination setting. Everolimus given as monotherapy resulted in downregulation of different proteins involved in DNA damage repair, including FANCD2, RAD50 and SUV39H1. In the combination setting, expression of these proteins was almost completely abolished, suggesting convergence of PARP and mTOR in downregulation of DNA damage repair components. In conclusion, our results suggest that combining mTOR and DNA repair inhibition could be a successful strategy to treat a subset of breast cancer with BRCA2 mutation and alterations in the PI3K/AKT/mTOR pathway.

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Wulfran Cacheux, Petros Tsantoulis, Adrien Briaux, Sophie Vacher, Pascale Mariani, Marion Richard-Molard, Bruno Buecher, Sophie Richon, Emmanuelle Jeannot, Julien Lazartigues, Etienne Rouleau, Odette Mariani, Elsy El Alam, Jérôme Cros, Sergio Roman-Roman, Emmanuel Mitry, Elodie Girard, Virginie Dangles-Marie, Astrid Lièvre, Ivan Bièche (2018 May 28)

Array comparative genomic hybridization identifies high level of PI3K/Akt/mTOR pathway alterations in anal cancer recurrences.

Cancer medicine : DOI : 10.1002/cam4.1533 En savoir plus
Résumé

Genomic alterations of anal squamous cell carcinoma (ASCC) remain poorly understood due to the rarity of this tumor. Array comparative genomic hybridization and targeted gene sequencing were performed in 49 cases of ASCC. The most frequently altered regions (with a frequency greater than 25%) were 10 deleted regions (2q35, 2q36.3, 3p21.2, 4p16.3, 4p31.21, 7q36.1, 8p23.3, 10q23.2, 11q22.3, and 13q14.11) and 8 gained regions (1p36.33, 1q21.1, 3q26.32, 5p15.33, 8q24.3, 9q34.3, 16p13.3, and 19p13.3). The most frequent minimal regions of deletion (55%) encompassed the 11q22.3 region containing ATM, while the most frequent minimal regions of gain (57%) encompassed the 3q26.32 region containing PIK3CA. Recurrent homozygous deletions were observed for 5 loci (ie, TGFR2 in 4 cases), and recurrent focal amplifications were observed for 8 loci (ie, DDR2 and CCND1 in 3 cases, respectively). Several of the focal amplified genes are targets for specific therapies. Integrated analysis showed that the PI3K/Akt/mTOR signaling pathway was the pathway most extensively affected, particularly in recurrences compared to treatment-naive tumors (64% vs 30%; P = .017). In patients with ASCC recurrences, poor overall survival (OS) was significantly correlated with a large number of altered regions (P = .024). These findings provide insight into the somatic genomic alterations in ASCC and highlight the key role of the druggable PI3K/Akt/mTOR signaling pathway.

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