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Molecular Mechanisms of Cancer and Stemness Lluís Espinosa

  The Molecular Mechanisms of Cancer and Stemness group is fully dedicated to the identification of elements and pathways that regulate Stem Cell and Cancer Stem Cell homeostasis, with the final goal of discovering biomarkers and therapeutic targets for regenerative medicine and cancer.

The group has historically focused on studying the Notch and NF-κB pathways, which are principal actors of these processes. However, our research now aims to integrate these pathways in the context of other important signals for stem cell and cell transformation such as BRAF or β-catenin.

Thus our current interest lays on two different subjects: 1) the identification of the cellular compartments that are regulated by PS-IκBα and the mechanisms supporting this selectivity, and 2) the investigation of p45-IKKα function in stem cells, tissue homeostasis and oncogenic transformation, mainly through the identification and characterization of its phosphorylation targets and the genomic regions that are substrates for p45-IKKα.

To achieve our objectives, we are setting up a variety of cutting-edge in vivo and in vitro models including 3D cultures for intestinal stem cells (miniguts), tissue-specific and/or inducible knock out and transgenic mice lines, and reporter animals for stem cell and tumor cell lineage tracing experiments.

Relevant bibliography of the group:

• Espinosa L, Cathelin S, D'Altri T, Trimarchi T, Statnikov A, Guiu J, Rodilla V, Inglés-Esteve J, Nomdedeu J, Bellosillo B, Besses C, Abdel-Wahab O, Kucine N, Sun SC, Song G, Mullighan CC, Levine RL, Rajewsky K, Aifantis I, Bigas A. The Notch/Hes1 Pathway Sustains NF-κB Activation through CYLD Repression in T Cell Leukemia. Cancer Cell. 2010 Sep 14;18(3):268-81
• Margalef P, Fernández-Majada V, Villanueva A, Garcia-Carbonell R, Iglesias M, López L, Martínez-Iniesta M, Villà-Freixa J, Mulero MC, Andreu M, Torres F, Mayo MW, Bigas A*, Espinosa L* (*equal contribution). A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer. Cell Rep. 2012 Oct 25;2(4):840-54
• Mulero MC, Ferres-Marco D, Islam A, Margalef P, Pecoraro M, Toll A, Drechsel N, Charneco C, Davis S, Bellora N, Gallardo F, López-Arribillaga E, Asensio-Juan E, Rodilla V, González J, Iglesias M, Shih V, Mar Albà M, Di Croce L, Hoffmann A, Miyamoto S, Villà-Freixa J, López-Bigas N, Keyes WM, Domínguez M, Bigas A, Espinosa L. Chromatin-Bound IκBα Regulates a Subset of Polycomb Target Genes in Differentiation and Cancer. Cancer Cell. 2013 Aug 12;24(2):151-66
• López-Arribillaga E, Rodilla V, Pellegrinet L, Guiu J, Iglesias M, Roman AC, Gutarra S, González S, Muñoz-Cánoves P, Fernández-Salguero P, Radtke F, Bigas A, Espinosa L. Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch. Development. 2015 Jan 1;142(1):41-50
• Margalef P, Colomer C, Villanueva A, Montagut C, Iglesias M, Bellosillo B, Salazar R, Martínez-Iniesta M, Bigas A, Espinosa L. BRAF-induced tumorigenesis is IKKα-dependent but NF-κB-independent. Science Signaling, 2015 Apr 21;8(373)