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3. Enhanced wild-Type mET Receptor levels in mouse hepatocytes attenuates insulin-mediated signaling

Author

Rada, Patricia, Lamballe, Fabienne, Cárcer, Guillermo de, Carceller-López, Elena, Hitos, Ana B., Sequera, Celia, Maina, Flavio, Valverde, Ángela M., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Fundación Ramón Areces, Instituto de Salud Carlos III, Institut National du Cancer (France), Aix-Marseille Université, Fondation de France, Fondation ARC pour la Recherche sur le Cancer, Instituto de Investigaciones Biomédicas Alberto Sols [Madrid], CSIC-UAM, Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)

Subjects
MET, insulin signaling, hepatocytes, glucose homeostasis, [SDV]Life Sciences [q-bio], General Medicine, Glucose homeostasis, Insulin signaling, Mice, Glucose, Hepatocytes, Animals, Insulin, Insulin Resistance, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Compelling evidence points to the MET receptor tyrosine kinase as a key player during liver development and regeneration. Recently, a role of MET in the pathophysiology of insulin resistance and obesity is emerging. Herein, we aimed to determine whether MET regulates hepatic insulin sensitivity. To achieve this, mice in which the expression of wild-type MET in hepatocytes is slightly enhanced above endogenous levels (Alb-R26Met mice) were analyzed to document glucose homeostasis, energy balance, and insulin signaling in hepatocytes. We found that Alb-R26Met mice exhibited higher body weight and food intake when compared to R26stopMet control mice. Metabolic analyses revealed that Alb-R26Met mice presented age-related glucose and pyruvate intolerance in comparison to R26stopMet controls. Additionally, in Alb-R26Met mice, high MET levels decreased insulin-induced insulin receptor (IR) and AKT phosphorylation compared to control mice. These results were corroborated in vitro by analyzing IR and AKT phosphorylation in primary mouse hepatocytes from Alb-R26Met and R26stopMet mice upon insulin stimulation. Moreover, co-immunoprecipitation assays revealed MET-IR interaction under both basal and insulin stimulation conditions; this effect was enhanced in Alb-R26Met hepatocytes. Altogether, our results indicate that enhanced MET levels alter hepatic glucose homeostasis, which can be an early event for subsequent liver pathologies., This work was supported by the Spanish Ministry of Science and Innovation with the help of European FEDER funding (RTI2018-094052-B-100), Comunidad de Madrid, Spain (S2017/BMD3684), and Fundación Ramón Areces and CIBERDEM (ISCIII) to Á.M.V. P.R. was a recipient of an International Mobility Grant from CIBERDEM (ISCIII). C.S. was supported by a FRM fellowship. F.M. is supported by research funding from Institut National du Cancer, ITMO Cancer Aviesan and INCa within the framework of the 2021–2030 Cancer Control Strategy on funds administered by Inserm, Canceropôle Provence Alpes Côte d’Azur, Institute for Cancer and Immunology (Aix-Marseille University), GEFLUC—Les Entreprises contre le Cancer, FdF (Fondation de France), ARC (Association pour la Recherche sur le Cancer), and SATT Sud-Est. The contribution of the Region Provence-AlpesCôte d’Azur and of the Aix-Marseille Univ to the IBDM animal facility is acknowledged.

Published
2022

5. Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Author

Lamballe, Fabienne, primary, Ahmad, Fahmida, additional, Vinik, Yaron, additional, Castellanet, Olivier, additional, Daian, Fabrice, additional, Müller, Anna‐Katharina, additional, Köhler, Ulrike A., additional, Bailly, Anne‐Laure, additional, Josselin, Emmanuelle, additional, Castellano, Rémy, additional, Cayrou, Christelle, additional, Charafe‐Jauffret, Emmanuelle, additional, Mills, Gordon B., additional, Géli, Vincent, additional, Borg, Jean‐Paul, additional, Lev, Sima, additional, and Maina, Flavio, additional

Published
2020
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7. Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance.

Author

Lamballe, Fabienne, Ahmad, Fahmida, Vinik, Yaron, Castellanet, Olivier, Daian, Fabrice, Müller, Anna‐Katharina, Köhler, Ulrike A., Bailly, Anne‐Laure, Josselin, Emmanuelle, Castellano, Rémy, Cayrou, Christelle, Charafe‐Jauffret, Emmanuelle, Mills, Gordon B., Géli, Vincent, Borg, Jean‐Paul, Lev, Sima, and Maina, Flavio

Subjects
*TRIPLE-negative breast cancer, *DRUG resistance, *MET receptor, *HETEROGENEITY, *BREAST cancer
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. [ABSTRACT FROM AUTHOR]

Published
2021
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9. Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling

Author

Hultberg, Anna, primary, Morello, Virginia, additional, Huyghe, Leander, additional, De Jonge, Natalie, additional, Blanchetot, Christophe, additional, Hanssens, Valérie, additional, De Boeck, Gitte, additional, Silence, Karen, additional, Festjens, Els, additional, Heukers, Raimond, additional, Roux, Benjamin, additional, Lamballe, Fabienne, additional, Ginestier, Christophe, additional, Charafe-Jauffret, Emmanuelle, additional, Maina, Flavio, additional, Brouckaert, Peter, additional, Saunders, Michael, additional, Thibault, Alain, additional, Dreier, Torsten, additional, de Haard, Hans, additional, and Michieli, Paolo, additional

Published
2015
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11. Combined Drug Action of 2-Phenylimidazo[2,1-b]Benzothiazole Derivatives on Cancer Cells According to Their Oncogenic Molecular Signatures

Author

Furlan, Alessandro, primary, Roux, Benjamin, additional, Lamballe, Fabienne, additional, Conti, Filippo, additional, Issaly, Nathalie, additional, Daian, Fabrice, additional, Guillemot, Jean-François, additional, Richelme, Sylvie, additional, Contensin, Magali, additional, Bosch, Joan, additional, Passarella, Daniele, additional, Piccolo, Oreste, additional, Dono, Rosanna, additional, and Maina, Flavio, additional

Published
2012
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15. Pool-Specific Regulation of Motor Neuron Survival by Neurotrophic Support.

Author

Lamballe, Fabienne, Genestine, Matthieu, Caruso, Nathalie, Arce, Vilma, Richelme, Sylvie, Helmbacher, Françoise, and Maina, Flavio

Subjects
*MOTOR neurons, *MUSCLES, *HEPATOCYTE growth factor, *CELL receptors, *NEUROTROPHIC functions, *NEUROPHYSIOLOGY
Abstract

The precise control of motor neuron (MN) death and survival following initial innervation of skeletal muscle targets is a key step in sculpting a functional motor system, but how this is regulated at the level of individual motor pools remains unclear. Hepatocyte growth factor (HGF) and its receptor Met play key developmental roles in both muscle and MNs. We generated mice (termed "Nes-Met") in which met is inactivated from midembryonic stages onward in the CNS only. Adult animals showed motor behavioral defects suggestive of impaired innervation of pectoral muscles. Correspondingly, in neonatal spinal cords of Nes-Met mutants, we observed death of a discrete population of pea3-expressing MNs at brachial levels. Axonal tracing using pea3 reporter mice revealed a novel target muscle of pea3-expressing MNs: the pectoralis minor muscle. In Nes-Met mice, the pectoralis minor pool initially innervated its target muscle, but required HGF/Met for survival, hence for proper maintenance of muscle innervation. In contrast, HGF/Met was dispensable for the survival of neighboring Met-expressing MN pools, despite its earlier functions for their specification and axon growth. Our results demonstrate the exquisite degree to which outcomes of signaling by receptor tyrosine kinases are regulated on a cell-by-cell basis. They also provide a model for one way in which the multiplicity of neurotrophic factors may allow for regulation of MN numbers in a pool-specific manner. [ABSTRACT FROM AUTHOR]

Published
2011
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