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Institut de Génétique Moléculaire de Montpellier (IGMM) - UMR5535


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Home page > Research Groups > Michael HAHNE - Inflammation & Cancer

Michael HAHNE - Inflammation & Cancer

Our group has a long-standing focus on Tumor Necrosis Factor (TNF) family members, which are important regulators of the immune system. Deregulated expression or function of a TNF family member is frequently associated with disease development including tumorigenesis and inflammation. In the recent years we extended our knowledge in colorectal carcinoma, and inflammatory diseases that initiated new collaborations within the IGMM as well as external ones (national and European), and notably include clinicians and biotech companies.

We have a particular interest in the TNF-like ligand APRIL (A Proliferation-Inducing Ligand), that we originally identified as a cytokine capable of promoting B cell malignancies (Planelles et al. Cancer Cell ; 2004) and, more recently, also colorectal cancer (CRC). In fact, we could demonstrate that APRIL promotes CRC in two independent mouse models (Lascano et al. Cell Death Diff ; 2012). Subsequently we found that circulating APRIL levels are correlated with advanced disease and prognosis in rectal cancer patients. Unexpectedly, we discovered that APRIL also has immunoregulatory capacities by stimulating regulatory B cells, thus dampening inflammation in various mouse models including collagen-induced arthritis (Fernandez et al. ARD ; 2013). Notably, this interferes with the present believe that APRIL is an inflammation promoting factor and, in the meantime, clinical trails for the use of APRIL antagonists in inflammatory diseases have been abandoned. We are now characterizing the mechanisms that trigger the inflammation-dampening effect of APRIL with the perspective to develop novel therapeutic strategies for dampening inflammation. Following our discovery that APRIL drives immunoregulatory B cells in mice, we are presently testing whether APRIL could also promote the therapeutic potential of regulatory B cells in human pathologies. Notably, our work on inflammatory diseases is strengthened by the established integration of clinicians from the immunorheumatology department of the CHU Montpellier. This has allowed us to establish a bank of peripheral blood mononuclear cells and sera of well-characterized rheumatoid arthritis patients before and during treatment. We are using these samples in identifying predictive markers for treatments in collaboration with academic and biotech partners.

Our previous work on CRC initiated a new line of research in our lab that focuses on the role of tubulin modifying enzymes in carcinogenesis. In collaboration with Carsten Janke (Institute Curie, Orsay) we identified an unexpected role of the tubulin glycylase TTLL3 in the regulation of colon homeostasis and tumorigenesis (Rocha et al. EMBO ; 2014). Specifically, we discovered that colonic epithelial cells express TTLL3 and in the absence of TTLL3, displayed decreased numbers of primary cilia and an increased proliferation rate. Finally, we demonstrated that TTLL3-deficient mice, which display no obvious abnormalities in the steady state, are more susceptible to chemically induced colon carcinogenesis. Notably, we have found that TTLL3 expression levels are significantly downregulated in primary colorectal carcinomas and matched metastases when compared to those of matched normal colon tissues. These data unambiguously demonstrate that TTLL3 is linked to CRC progression via the downregulation of its expression in colon carcinomas. We are presently, extending these findings by analyzing the role of other tubulin modifying enzymes in CRC.

Loss of TTLL3 results in increased proliferation of colon epithelium. Cell proliferation in colon crypts was analyzed by incorporation of BrdU.

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Institut de Génétique Moléculaire de Montpellier
CNRS-UMR 5535 - 1919, Route de Mende - 34293 Montpellier  Cedex 5
FRANCE
(+33) 04 34 35 96 01