Apical–basal polarity is critical to ensuring functional integrity of the glandular architecture and organ specificity. The establishment of epithelial polarity involves cell-cell and cell-ECM interactions, as well as an intensive trafficking of membrane components. There is an intimate relationship between a loss of polarity and the development of diseases such as cancer and infections. However, the way in which these events are coupled remains an important issue.
Phosphoinositides are structural determinants of the cell membrane, important signalling molecules and key mediators of the membrane fusion required for intra cellular vesicular movements and cell polarity. Our work has demonstrated a new concept regarding the key role of the spatio-temporal distribution of phosphoinositides during cell polarization.
Moreover, ongoing work in our laboratory has indicated that septins are highly expressed in different liver cancers. Septins are an evolutionarily conserved family of GTP-binding proteins, initially described regarding their role in cytokinesis. However, septins have now emerged as key regulators of vesicle trafficking, invasion and polarity. They also regulate microtubule and actin dynamics and bind to phosphoinositides.
Our research programme focuses on the roles of phosphoinositides and septin 9 in membrane trafficking, cell migration and polarisation, from two pathological standpoints:
- the development of cholanciocarcinoma and metastasis, and
- the cellular propagation of hepatitis C virus and the development of hepatocellular carcinoma.
Development of cholangiocarcinoma and metastasis
Cholangiocarcinoma (CCA) is a rare malignant tumor increasing in frequency worldwide. CCA has the worst prognosis of any tumor arising in the liver; its 5-year survival is poor, and it is accompanied by a high recurrence rate. Aggressive surgery is the only choice of curative therapy. Unfortunately, only a few patients are suitable for surgery due to the lack of early detection of CCA. CCA arises from the polarized epithelial cells (cholangiocytes) lining intrahepatic bile ducts. Our aim is to understand the mechanisms that drive highly polarized cholangiocytes transition towards malignant phenotype and invade other tissues.
VHC Cellular propagation and Hepatocarcinoma developpement
Cellular propagation of Hepatitis C virus and the development of hepatocellular carcinoma.
Hepatitis C virus (HCV) is a major causal agent of chronic liver infection; indeed there is a high risk that infected subjects will develop cirrhosis and liver carcinoma.
During viral biosynthesis, an association of viral particles with lipid droplets has been reported. This interaction is crucial to both particle assembly and viral infection. HCV mainly infects hepatocytes, which are highly polarised epithelial cells. We therefore propose that HCV may be able to highjack phosphoinositide metabolism and polarity mechanisms in order to invade and propagate in the host cell, leading to a loss of polarity and the development of carcinogenesis. The objective of our studies is to define molecular targets for the early diagnosis and therapy of these liver diseases.
Publications
- Gassama-Diagne A, Payrastre B. Phosphoinositide signaling pathways: promising role as builders of epithelial cell polarity. Int Rev Cell Mol Biol 2009;273:313-43.
- Sobesky R, Feray C, Rimlinger F, Derian N, Dos Santos A, Roque-Afonso AM, Samuel D, Bréchot C, Thiers V. Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection. Hepatology 2007 46(6):1704-12.
- Martin-Belmonte F, Gassama A, Datta A, Yu W, Rescher U, Gerke V, Mostov K. PTEN-Mediated Apical Segregation of Phosphoinositides Controls Epithelial Morphogenesis through Cdc42. Cell 2007; 128, 383-397.
- Kierbel A, Gassama-Diagne A, Rocha C, Radoshevich L, Olson J, Mostov K, Engel J. Pseudomonas Aeruginosa exploits a PIP3-dependent pathway to transform apical into basolateral membrane. J. Cell.biol. 2007; 177, 1, 21-27.
- Dos Santos A, Thiers V, Sar S, Derian N, Bensalem N, Yilmaz F, Bralet MP, Ducot B, Bréchot C, Demaugre F. Contribution of laser microdissection-based technology to proteomic analysis in hepatocellular carcinoma developing on cirrhosis. Proteomics - Clinical Applications 2007; 1, 545-554.
- Gassama-Diagne A, Yu W, ter Beest M, Martin-Belmonte F, Kierbel A, Engel J, Mostov K. Phosphatidylinositol-3,4,5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells. Nature Cell Biology 2006; 8, 963 – 970.