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    UCP2 and tumor development

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    Principal investigator : M-Clotilde Alves-Guerra

    Contact : – Phone : +33 1 53 73 27 06

     

     

     Objective

     

    UCP2 (uncoupling protein 2), the second member identified in the UCP family, has cellular functions that remain the matter of debate. Our team has shown that UCP2 regulates cell energetic metabolism and reactive oxygen species production and is involved in inflammation. The main goal of our project is to determine whether these functions of UCP2 can play a role in tumor development. Through that approach we address the impact of energy metabolism and oxidative stress in cell proliferation and resistance to cell death, both crucial cellular determinants for tumorigenesis, with the prospect to identify new targets and / or strategies to treat cancer.

    The group

    Daniel Ricquier, PU-PH, Tiphaine Sancerni, M2 and a post-doctoral fellow who will be hired in June 2015 are involved in the project.

     

    Research interests

     

    Our main interest is to study whether interfering with cellular energetic metabolism, especially within mitochondria, represents a therapeutic avenue for cancer. To that purpose we use modulation of UCP2. Using cells derived from the Ucp2-/- mouse model obtained in the team, we have shown that UCP2 plays a role in cell proliferation (Pecqueur et al., 2008). Recently we demonstrated in cancer cells that UCP2 overexpression decreases proliferation and tumorigenic potential while modifying the energetic metabolism towards increased oxidative phosphorylation and decreased glycolysis (Esteves et al., 2014). UCP2 thus appears a key regulator of cellular metabolism with relevant action against the maintenance of tumor malignancy. It therefore represents a good tool to understand the cross talk between cell metabolism on the one hand and initiation, progression and, on the other hand, invasion events that promote cancer.

    This project is developed in two directions using the Ucp2-/- mouse model available in the team. Our first goal is to show whether UCP2 is able to control the initiation and tumor progression in intestinal cancer models. Our second goal is to dissect out the role of UCP2 in the immune and non-immune tumor microenvironment, which both influence tumor initiation and development.

    Following the results obtained in mice, it will be interesting to explore the expression of UCP2 in invasive and / or drug resistance tumors in humans. That project will have to take into account that, as demonstrated by an earlier work of the team (Pecqueur et al, J Biol Chem 2001;276(12):8705), the steady-state level of UCP2 protein is regulated at a post-transcriptional level.

     

    Main publications

     Bertolin G, Bulteau AL, Alves-Guerra MC, Burel A, Lavault MT, Gavard O, Le Bras S, Gagné JP, Poirier GG, Le Borgne R, Prigent C, Tramier M. Aurora kinase A localises to mitochondria to control organelle dynamics and energy production. Elife. 2018 Aug 2;7. pii: e38111 (sous presse)

    Bricambert J, Alves-Guerra MC, Esteves P, Prip-Buus C, Bertrand-Michel J, Guillou H, Chang CJ, Vander Wal MN, Canonne-Hergaux F, Mathurin P, Raverdy V, Pattou F, Girard J, Postic C, Dentin R. The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity. Nat Commun. 2018 May 29;9(1):2092.

    Senni N, Savall M, Cabrerizo Granados D, Alves-Guerra MC, Sartor C, Lagoutte I, Gougelet A, Terris B, Gilgenkrantz H, Perret C, Colnot S, Bossard P. β-catenin-activated hepatocellular carcinomas are addicted to fatty acids. Gut. 2018 Apr 12. pii: gutjnl-2017-315448.

    Hirose M, Schilf P, Rohde S, Gupta Y, Sancerni T, Alves-Guerra MC, Sina C, Jaster R, Miroux B, Ibrahim SM. The mitochondrial uncoupling protein 2 gene is causal for the spontaneous polycystic liver diseases in mice. Mitochondrion. 2017 Nov 14. pii: S1567-7249(17)30203-9.

    Broche B, Ben Fradj S, Aguilar E, Sancerni T, Bénard M, Makaci F, Berthault C, Scharfmann R, Alves-Guerra MC*, Duvillié B*. Mitochondrial Protein UCP2 Controls Pancreas Development. Diabetes. 2018 Jan;67(1):78-84. *auteurs correspondants

    Bouillaud F, Alves-Guerra MC, Ricquier D. UCPs, at the interface between bioenergetics and metabolism. Biochim Biophys Acta. 2016 Oct;1863(10):2443-56.

    Esteves P*, Pecqueur C* and Alves-Guerra MC. UCP2 induces a metabolic reprogramming to inhibit proliferation of cancer cells. Molecular & Cellular Oncology 2015 2(1) e975024 * premiers auteurs équivalents

    Esteves P, Pecqueur C, Ransy C, Esnous C, Lenoir V, Bouillaud F, Bulteau AL, Lombes A, Prip-Buus C, Ricquier D, and Alves-Guerra MC. Mitochondrial retrograde signaling mediated by UCP2 inhibits cancer cell proliferation and tumorigenesis. Cancer Research 2014 74(14):3971-821. Issue’s Cover.

    Pecqueur C, Alves-Guerra C, Ricquier D, Bouillaud F. UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism ? IUBMB Life. 2009 Jul; 61(7):762-7.

    Pecqueur C, Bui T, Gelly C, Hauchard J, Barbot C, Bouillaud F, Ricquier D, Miroux B, Thompson CB. Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization. FASEB J. 2008 Jan;22(1):9-18.

     

     

    Past members

     

    Pauline Esteves - PhD (2011-2014)

     

    Financial supports

    These programs are supported by Cancéropôle Ile-de-France