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Inflammation and Cancer

Michael Hahne

Research projects

Our group has been working for more than fifteen years on the role of TNF family members in immunity and diseases, notably APRIL (A Proliferation Inducing Ligand). For this, we established various mouse models that allow to study tumorigenesis and inflammation.

We have a long-standing 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, in collaboration with Jan Paul Medema (AMC, Amsterdam) we could demonstrate that APRIL promotes CRC in two independent mouse models (Lascano et al. Cell Death Diff; 2012). For this, we used two well-established models for CR cancerogenesis: a genetic model of tumor-suppressor deficiency (ApcMin mice) as well as a chemically-induced colitis-associated colon cancer (CAC) model. We described that ectopic APRIL expression in mice increases the initiation and growth of tumors in both CRC models. Furthermore, knockdown of APRIL in primary spheroid cultures of colon cancer cells and a CRC cell line reduced tumor clonogenicity and in vivo outgrowth. 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. We found, that similar to mice, different B cell subsets in human are prone to produce IL-10 and that the number of IL-10 producing B cells is significantly lower in RA patients compared with healthy subjects strongly suggesting that Breg cell deficiency promotes disease development in RA (Daien et al. Arthritis Rheumatol; 2014). Our observation that Breg cells are functional in RA patients argues for the restoration of normal Breg cell numbers in these patients as a novel therapeutic strategy. More recently, we found that APRIL stimulates IL-10 production by human B cells in vitro, underlining the potential role of APRIL in immunoregulatory functions in humans (Hua et al. J Autoimmun; 2016). Notably, our work on inflammatory diseases is strengthened by the established integration of clinicians from the immunorheumatology department of the University Hospital (CHU) Montpellier.

The expertise we gained in colitis-associated colon cancer initiated various collaborations.

Notably our group 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 and fibroblasts express TTLL3 and started to generate cell specific knock-out mice to understand how TTLL3-deficiency promotes CAC. The absence of TTLL3 in displayed decreased numbers of primary cilia in the colon. 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.

Figure 1: Colonic mouse fibroblasts were isolated and stained for alphaSMA (green) and vimentin (red). Nuclei were with Hoechst 33342 (blue).
 
 

More recently, we started to collaborate with the Tazi group and the collaborative CNRS/ABIVAX laboratory. This laboratory has generated pharmaceutical inhibitors and together we are presently evaluating their potential to dampen inflammation using relevant mouse models (Chebli et al. Sci Rep; in press).

Members

Team leader

Michael HAHNE

Chercheur DR2

(+33) 04 34 35 96 39

102

Julie BREMOND

AI-Recherche

+33 (0)4 34 35 96 39

Monica GABOLA

Doctorant

+33 (0)4 34 35 96 39

Benedicte LEMMERS

CRCN

(+33) 04 34 35 96 39

102

Conception PAUL

IE-Recherche

(+33) 04 34 35 96 39

102

Valerie PINET

CRCN

(+33) 04 34 35 96 39

117

Alexandra POCHMANN

Stagiaire

+33 (0)4 34 35 96 39

102

Hulya TURALI

AI-Recherche

+33 (0)4 34 35 96 39

Selected Publications

More information

Funding

We are grateful to the following funding institutions, which supported us in the recent years:

AICR

ARC

Arthritis Foundation Courtin

Chougai

Fondation de France

FRM

INCA

Pfizer

SFR

SIRIC

Société Française de Rhumatologie

UCB

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Team Overview
Model organism studied
Cell and tissue specific knock-out mice, biospies of patients (i.e. tissue sections from colorectal cancer patients, peripheral blood cells and synovial fibroblasts from Rheumatoid arthritis patients)
Biological process
Colon homeostasis and carcinogenesis, inflammation (i.e. Rheumatoid arthritis)
Biological techniques
Classical biochemical and cell biological techniques, FACS, convocal microscopy, immunohistochemistry, RNAseq