• E-mail :[email]
  • Phone : +33 2 23 23 38 52
  • Location : Rennes, France
Last update 2022-02-14 10:21:08.958

Bruno CLEMENT Inserm Research Director, PhD Cell and Molecular Biology

Course and current status

Present address

INSERM U1241, INRAe U1341

Institute of Nutrition, Metabolisms and Cancer

Rennes University-Hospital

University of Rennes                    

F-35033 RENNES




- 1980: Master in Cell Biology and Physiology, University of Nantes

- 1982: Medical Biology, St Louis-Lariboisière, Paris

- 1986: Ph.D. award from the University of Rennes I

Post-doctoral Experience 

- 1987-1989: Post-doctoral fellow in the Laboratory of Developmental Biology and Anomalies (Head: Pr. George Martin), National Institutes of Health, Bethesda MD

- 1991, 1992: Visiting fellow, National Institutes of Health, Bethesda MD, USA


- 1992: Director of Research INSERM, Liver Unit, INSERM U-49

- 1997: Director of Research INSERM, Detoxication and Tissue Repair Unit INSERM U-620

- 1998-2003: Deputy Director of the Biotechnology Department, Ministry of Research

- 2003-2008: Counselor of the General Director of Inserm and Scientific Director of INSERM-Transfert

- 2008-present: Associate researcher, KRIBB, Daejon, South-Korea

- 2010-2016: Head of the INSERM Unit n°991 “Liver, Metabolisms and Cancer”

- 2017-2021 Head of the Institute "Nutrition, Metabolisms and Cancer" (Inserm-Inrae-Univ Rennes)

Research administration

- 1991-1994: INSERM Scientific committee:  Hepatology, Nutrition, and Metabolism.

- 1995-1998: Advisory committee on Xenotransplantation

- 1994-2006: Chairman of the local Ethics Committee (CPP), Rennes University Hospital

- 1999-2007: Scientific steering committee of Association de la Recherche contre le Cancer

- 1999-2006: European expert: PCRDT, DG XII

- 1999-2002: Head of the French delegation at the OECD, Biotechnology

- 2005-2009: Scientific committee of Rennes Medical School

- 2007-2008: European expert of the ERC programme

- 2007-2010: Chairman of the National Committee for Biological Resources

- 2007-2019: Chairman of the national committee for the AFNOR standard of Biological resources centers (norms : NFS 96-900 and ISO 20387).

- 2007-2016: Scientific advisory board of the National Infrastructures Committee (GIS IBiSA)

- 2011-2015: Member of the CNU, Cell Biology section

- 2011-2015: European expert of the ICT programme

- 2011-2017: CSO of the National Biobank Infrastructure

- 2014-2017 : Scientific advisor for biobanks at the Institut Pasteur International Network

- 2011-present: member of the INSERM Institutional Review Board

- 2013-present: scientific advisory board of the CONSTANCES cohort

- 2021-present: member of the Ethical and scientific committee of the Health data hub (CESRESS)

Awards and Honors

1998: award of the National Academy of Medicine

2002: Chevalier dans l’Ordre National du Mérite

2007: KRIBB award (South-Korea)

2017 : National Academy of Medicine (corresponding member)

Scientific Field

Memberships: International Liver Cancer Association, American Association for the Study of Liver Diseases, European Association for the Study of Liver Diseases

Editorial board: Hepatology (1997-2007), Word Journal of Gastroenterology (2003-2011)

Web of Science ResearcherID  E-5546-2016

ORCID 0000-0001-8827-146X

228 publications (ISI WoS data base: 8157 citations; h-index=46)

7 other publications

25 publications in books

132 invited conferences

7 patents

Most cited papers: Hudson et al. Nature 2010; Guichard et al. Nature Genet. 2012; Guguen-Guillouzo et al. Exp. Cell Res. 1983; Clément et al. Hepatology 1986; Garin et al. J.Nucl.Med 2012; Clément et al. Hepatology 1984; Le Pabic et al. Hepatology 2003; Théret et al. Hepatology 2001; Coulouarn et al. Cancer Res. 2012; Garin et al. EJNMMI 2013;  Kleinman et al. Arch. Biochem. Biophys. 1991; Clément et al. J Cell Biol. 1990;  Théret et al. Hepatology 1999; Abdel-Aziz et al. Am. J. Pathol. 1990

Scientific summary

The main fields of investigation of my group include: hepatic fibrogenesis, the cellular and molecular mechanisms involved in this process, its impact on hepatocyte functions, its role in hepatocellular carcinoma formation and progression, as well as diagnostic and therapeutic tools which can derive from these findings.

Extracellular matrix in both normal and pathological livers. We have been among the first groups worldwide: (i) to characterize the main components of the hepatic extracellular matrix and their changes in fetal livers, in fibrotic/cirrhotic livers and in liver cancers; (ii) to identify cells involved in extracellular matrix formation, including the central role of hepatic stellate cells in fibrogenesis (Cell. Mol. Biol. 1984; J. Histochem. Cytochem. 1985; Hepatology 1986, 1988, 1991; Am. J. Pathol. 1990: Gastroenterology 1992; Am. J. Pathol. 1993 ; FEBS Lett. 1991). We have also shown that fibrogenesis is reversible when removing the causal agent of liver injury (Am. J. Pathol. 1990, J. Pathol. 1991).

Biological effects of extracellular matrix on hepatocytes. Technological breakthroughs in both hepatocyte and stellate cells isolation (from both rodents and humans since 1982 in our group), allowed us to investigate the role of both complex and purified matrices on survival, proliferation and function of both normal and transformed hepatocytes. We have shown that both exogenous basement membranes and individual components, namely laminins were able to transiently modulate liver specific functions (Hepatology 1984, J. Cell. Physiol. 1994, J. Hepatol. 1995, Am. J. Pathol. 1993, 1997). When cocultured with biliary cells, the long-term maintenance of liver specific functions was associated with the deposition of a neoformed basement membrane (Hepatology 1984, Exp.Cell.Res 1983). Several components appeared to play a main role in this biological effect through specific receptors, including integrins, which interact with collagen IV, laminins and perlecan whose expression appeared dramatically changed in liver cancers (J. Biol. Chem. 1989, J. Cell Biol. 1990).

 Molecular mechanisms involved in fibrogenesis. We have set up two cell culture model systems in order to investigate the synthesis, deposition and turn-over of extracellular matrix ex vivo: (i) hepatic stellate cell primary cultures : when set up in conventional culture HSC are quiescent and then undergo dramatic changes towards a myofibroblastic phenotype ; they proliferate and express matrix components at high levels which however remain soluble in the medium ; (ii) when cocultured with hepatocytes, preexisting cell-cell interactions are restored. Unlike in conventional culture conditions, an abundant collagen-rich extracellular matrix is deposited in between both cell types. Both model systems allowed us to demonstrate that fibrogenesis depends on HSC phenotypic changes and that hepatocytes play a major role in matrix synthesis, deposition and turn-over: (i) the molecular mechanisms, including transcriptionnal factors of laminin g1 and collagen IV promoters were characterized (Biochem. J., 1996 ; Am. J. Pathol. 1997) ; (ii) matrix metalloproteinase-type 2 which is chiefly expressed by HSC is cleaved and activated through the formation of the ternary complex MMP2/TIMP2/MT1-MMP, and interaction with hepatocytes through the deposition of collagen I (Am. J. Pathol. 1997, Hepatology, 1999).

Extracellular matrix remodelling in liver cancers. Changes in the composition, distribution and synthesis of extracelular matrix components were analyzed in liver cancers. We have demonstrated the main role of both stromal cells and their interplays with hepatocytes in the imbalance between synthesis and degradation, at the forefront of tumour invasion (J. Hepatol. 1997, 1998; Am. J. Pathol. 1998). Importantly, tissue remodelling preceded invasion of metastases from gastrointestinal tumours in apparently normal livers, i.e. in the absence of detectable tumours, probably due to cytokines released from the primary tumour site (Int. J. Cancer 1997).

Modulation of cell signalling pathways by extracellular matrix in liver cancers.  Tissue remodeling is chiefly mediated through matrix metalloproteinases (Hepatology, 1999, 2003): MMPs modulate cell-cell and cell-matrix interactions, they are involved in the biodisponibility and/or shedding of cytokines and they release bioactive domains within extracellular matrix components (matricryptins). We have shown that stellate cells express ADAM-9 and ADAM-12 at high levels in fibrogenesis associated with hepatocellular carcinoma (HCC) progression. In vitro, TGFb induces both ADAM-12 and MMP2 overexpression (Hepatology 2003, J. Cell Biol 2007). Mutations in the MH2 domain of Smad 2 and 4 do not act as dominant negative, but down regulate TGFb response, through an overdegradation process which involves the proteasome (J Biol Chem. 2003).

We have been the first group to identify collagen XVIII as a main liver-collagen, with three different variants, including plasma and basement membrane-associated forms. We have shown that collagen XVIII is up-regulated in fibrotic liver and down regulated in HCC. In fibrosis and HCC, collagen XVIII can be cleaved into polypeptide-modules, including endostatin, a strong antiangiogenic factor in mice and the frizzled module FZC18 which modulates the Wnt-b catenin cell signaling pathway (Hepatology 1998, 1999, 2000, 2001, Cancer Res.2001). FZC18 (i) shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth; (ii) switches off the β-catenin target gene expression signature in vivo; and (iii) reduces the growth of human colorectal cancer xenografts by specifically controlling cell proliferation and cell cycle progression, without affecting angiogenesis or apoptosis (Oncogene 2012, PLOSOne 2011,2012, patent: PCT/EP2008/067779).

Hepatoma-stellate cells cross-talk increases the expression of pro-inflammatory cytokines, modifies the phenotype of hepatocytes toward motile cells, and generates a permissive pro-angiogenic microenvironment (Cancer Res. 2012). The expression of genes correlates with HCC progression in mice and is predictive of a poor prognosis and metastasis propensity in human HCC. Interestingly, the effects of crosstalk on migration and angiogenesis can be reversed by the histone deacetylase inhibitor trichostatin A (Cancer Res. 2012).

We have shown that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the porto-central axis in normal liver. Two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type β-catenin) and perivenous-type (mutant β-catenin) were characterized. A eight-gene periportal-type HCC signature was identified, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses (Hepatology 2017).

In mass-forming intrahepatic cholangiocarcinomas (ICC), a gene signature of 1,073 non-redundant genes significantly discriminated between non tumor fibrous tissue and tumor stroma. Alterations of components of extracellular signaling pathways predicted clinical outcome, and the expression of Osteopontin in ICC stroma was an independent prognostic factor for overall and disease-free survival (Hepatology 2013).

Image d’exemple