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    Intestinal epithelial cell proliferation in physiology and cancer

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    Group leader

     

     

    Phone number : +33 1 44 41 25 69
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    The aim of our group is to understand the factors regulating the rapid turnover of the intestinal epithelium also involved in intestinal tumorigenesis. We are investigating known signaling pathways such as the Wnt/b-catenin pathway and search for critical downstream events as well as novel signalings that act as drivers for intestinal homeostasis and cancer. Our experimental approach relies on a combination of mouse genetics, biopsies of patients with colorectal cancer (CRC), molecular and cellular biology and analyses at the pan-genomic scale. Identification of new drivers in the intestinal cancer development and progression is a major challenge not only to improve our fundamental knowledge but also to develop eventually diagnostic and therapeutic tools.

     

    The rapid self-renewing of the intestine is sustained by intestinal stem cell (ISC). It is well recognized that ISC and CRC biology are tightly linked in many aspects. It is generally thought that ISC are the cells of origin of CRC and crucial signaling pathways involved in ISC biology are often affected in CRC. The Wnt/b-catenin signaling highlights this paradigm. Its activation governs ISC function and its overactivation through Apc mutation is sufficient to initiate tumorigenesis.

     

     

     

    Main objectives

     

    ISC and their niches: Our previous work has demonstrated that the Wnt/b-catenin signaling regulates multiple aspects of intestinal physiology, including cell proliferation and differentiation into the Paneth cell lineage. Paneth cells support ISC by secreting Wnt. However nonepithelial Wnt signals could provide a secondary physiological source of Wnt in case of Paneth cell ablation. This result highlights a complex ISC niche. Our projects pursue the understanding of the factors required for the functional integrity of ISC by analyzing conditional knockout mutant mice and organoids culture.


    Signaling pathways involved in intestinal tumor initiation and progression: Aberrant activation of the Wnt/b-catenin signaling pathway is a major driving force of colorectal cancer. Approximately 80% of sporadic CRC show aberrant Wnt/b-catenin signaling activity as the result of mutation in APC. We have generated Apc knockout murine models to increase our understanding of the cancer development and progression. Our previous work has demonstrated that Apc loss is sufficient to initiate tumorigenesis. We have recently shown that autophagy, an intracellular catabolic pathway, is induced during all stages of CRC and appears to be required for cancer cells. Inhibition of autophagy prevents intestinal tumor development through a microbiome-induced immune responses and suppresses tumor progression by an alteration of the metabolism and the proliferation of cancer cells. Work in our lab continues to explore the significance of these signaling pathways in intestinal tumor biology.

    Main publications  

     

    Levy J, Cacheux W, Bara MA, L'Hermitte A, Lepage P, Fraudeau M, Trentesaux C, Lemarchand J, Durand A, Crain AM, Marchiol C, Renault G, Dumont F, Letourneur F, Delacre M, Schmitt A, Terris B, Perret C, Chamaillard M, Couty JP, Romagnolo B. Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth. Nat Cell Biol 2015;17:1062-73.

    Durand A, Donahue B, Peignon G, Letourneur F, Cagnard N, Slomianny C, Perret C, Shroyer NF, Romagnolo B. Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proc Natl Acad Sci U S A 2012;109:8965-70.

    Peignon G, Durand A, Cacheux W, Ayrault O, Terris B, Laurent-Puig P, Shroyer NF, Van Seuningen I, Honjo T, Perret C, Romagnolo B. Complex interplay between beta-catenin signalling and Notch effectors in intestinal tumorigenesis. Gut 2011;60:166-76.

    Andreu P, Peignon G, Slomianny C, Taketo MM, Colnot S, Robine S, Lamarque D, Laurent-Puig P, Perret C, Romagnolo B. A genetic study of the role of the Wnt/beta-catenin signalling in Paneth cell differentiation. Dev Biol 2008;324:288-96.

    Andreu P, Colnot S, Godard C, Laurent-Puig P, Lamarque D, Kahn A, Perret C, Romagnolo B. Identification of the IFITM Family as a New Molecular Marker in Human Colorectal Tumors. Cancer Res 2006;66:1949-1955.

    Andreu P, Colnot S, Godard C, Gad S, Chafey P, Niwa-Kawakita M, Laurent-Puig P, Kahn A, Robine S, Perret C, Romagnolo B. Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 2005;132:1443-1451.

     

    Team members

     

    Alumni :

    Levy Jonathan, doctorant (2010-2014)

    Medhi Ait-Bara, AI INSERM (2012-2013)

    Peignon Grégory, post-doctorant (2006-2010)

    Aurélie Durand, AI INSERM (2008-2011)

    Wulfran Cacheux, MD, doctorant (2007-2010)

    Pauline Andreu, doctorant (2002-2006)