The objective of the team is reached mainly through three research projects described below
UPR SIGNALING IN CANCER
For the past 10 years we have been investigating the role of IRE1 in glioma, the most frequent and lethal primary tumor of the brain. We have demonstrated that IRE1 is a key player in glioblastoma by conferring tumor cells specific aggressive features associated with remodeling of the tumor stroma (angiogenesis, immune infiltrate) and tumor cell migration/invasion properties (refs 1-6) (Figure 2).
We are currently delineating the specificity and selectivity of IRE1 RNase-dependent molecular mechanism in cancer cells and developing new models to investigate in vitro and in vivo the impact of selectively regulating this enzymatic activity for therapeutic purposes (refs 5, 8).
- 1) Drogat et al. (2007) Cancer Res. 2007 Jul 15;67(14):6700-7
- 2) Auf et al. (2010) Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15553-8
- 3) Dejeans et al. (2012) J Cell Sci. 2012 Sep 15;125(Pt 18):4278-87
- 4) Dejeans et al. (2014) Trends Mol Med. 2014 May;20(5):242-50
- 5) Pluquet et al. (2013) Cancer Res. 2013 Aug 1;73(15):4732-43
- 6) Pluquet et al. (2014) Ann Med. 2014 Jun;46(4):233-43
- 7) Higa et al. (2014) Mol Cell Biol. 2014 May;34(10):1839-49
- 8) Maurel et al. (2014) Trends Biochem Sci. 2014 May;39(5):245-54
Figure 2: IRE1 signaling confers aggressiveness to glioblastoma cells. (a-d) tumors generated after orthotopic implantation of human glioblastoma U87 cells either proficient (control) or deficient (IRE1 deficient) for IRE1 signaling in mouse brain. Control tumors (vimentin staining – green) are larger, more vascularized and more aggressive (c, e) than IRE1 signaling deficient tumors (d-e).
PROTEOSTASIS CONTROL IN GASTROINTESTINAL CANCERS
The objective of this project is to better understand the roles of proteostasis control (at the level of the ER) in GI cancers. In particular our project focuses on i) an ER resident member of the Protein Disulfide Isomerase family named AGR2 whose function still remain unclear but whose expression is upregulated in numerous adenocarcinoma (refs 1-3) and ii) the AAA+ ATPase p97 that plays a role in ER associated degradation (ERAD) and ER stress-induced transcription (refs 4-8). The expression of p97 is increased in hepatocellular carcinoma (ref 7).
- 1) Higa et al. (2011) J Biol Chem. 2011 Dec 30;286(52):44855-68
- 2) Higa et al. (2012) 2012 Aug;24(8):1548-55
- 3) Chevet et al. (2013) Oncogene. 2013 May 16;32(20):2499-509
- 4) Caruso et al. (2008) Mol Cell Biol. 2008 Jul;28(13):4261-74
- 5) Yi et al. (2012) Mol Cancer Ther. 2012 Dec;11(12):2610-20
- 6) Negroni et al. (2014) Mol Cell Proteomics. 2014 Dec;13(12):3473-83
- 7) Marza et al. (2015) EMBO Rep. 2015 Mar;16(3):332-40
Figure 3: Proteostasis in hepatocellular carcinoma - The incidence of hepatocellular carcinoma developed on non-fibrous livers (nfHCC) has increased over the past 10 years, however the mechanisms by which these tumors appear and progress remain unclear. We have used an integrative proteomics approach including quantitative proteomics and phosphoproteomics to shed light on the events occurring in human tumors. We have demonstrated that regulation of protein homeostasis represents a major event in nfHCC.
CHEMICAL BIOLOGY APPROACHES TO MODULATE ENDOPLASMIC RETICULUM PROTEOSTASIS VIA ALTERATION OF PROTEIN-PROTEIN INTERACTIONS
The objective of this project is to identify artificial modulators of the pathways described and characterized in the Projects 1 and 2. In particular we focus on the regulation of protein-protein interactions (PPi) within the ER proteostasis network using both in vitro (Alphascreen (Figure 3); refs 1-4) and cell-based approaches (refs 4-5). This project is carried out in collaboration with BMYscreen.
- 1) Taouji et al. (2009) Curr Genomics. 2009 Apr;10(2):93-101
- 2) Bouchecareilh et al. (2010) J Biomol Screen. 2010 Apr;15(4):406-17
- 3) Bouchecareilh et al. (2011) FASEB J. 2011 Sep;25(9):3115-29
- 4) Hetz et al. (2013) Nat Rev Drug Discov. 2013 Sep;12(9):703-19
- 5) Lievens et al. (2014) Mol Cell Proteomics. 2014 Dec;13(12):3332-42
Figure 3: Principles of the Alphascreen technology. Alphascreen is a bead-based non-radioactive and homogeneous detection technology. A signal is produced when the Alphascreen Acceptor and Donor beads are brought into proximity by a molecular interaction occurring between the binding partners captured on the beads. Laser excitation at 680 nm causes ambient oxygen to be converted to the singlet state by photosensitizers on the Donor bead. These react with chemiluminescent agents on the Acceptor bead only when the latter is in close proximity, emitting light at 520-620 nm.