Purdue University Center for Cancer Research, West Lafayette, In. USA
Contact IRCM : Charles Theillet
Université de Zurich, Suisse
Contact IRCM : Nathalie Bonnefoy
IGF, CNRS UMR5203, INSERM U1191, Montpellier
"Regulation by phosphorylation of two GPCRs targeted by antipsychotics"
Life Science Center, Vilnius University, Lithuania
'Targeting lipid rafts as a strategy against infection and cancer"
Short summary of the work:
Lipid rafts are membrane micro-domains that are enriched in cholesterol, sphingomyelin, sphingolipids and phospholipids. Their importance for living cells is underlined by their involvement in many processes including bacterial and viral entry, cardiovascular and prion diseases as well as cancer. Targeting lipid rafts is emerging as an innovative strategy to limit bacterial or viral infection and to increase the sensitivity to apoptosis of different types of tumours. Behind well-known cholesterol depleting agents (cyclodextrin) new compounds involved in cholesterol homeostasis were recently discovered. These potential drug candidates are capable to modify the lipid rafts composition and to alter the signalling platform associated with them. Multiple technologies including confocal microscopy to visualize lipid rafts, viability assays to determine the toxic effect of compounds on the cells, offer the opportunity to study in details the changes induced by this new class of cholesterol-targeting agents.
INSERM-U981 Institut Gustave Roussy, Villejuif.
"Collective epithelial-based metastases in colorectal carcinoma patients"
As a critical step in cancer progression and a challenge to patient treatment, tumour cell dissemination has been the subject of intense investigation across a range of model systems, in vitro and in animals. These studies have led to the assumption that the fatal progression of carcinoma is associated with a loss of epithelial architecture and polarity1-3 as single tumour cells escape from the primary tumour to reach secondary sites4,5. However, these studies have been performed using experimental model systems and the mechanisms driving metastatic spread in cancer patients remain under-investigated. Here, we collected and monitored over 50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastasis as it spreads to the peritoneum. This reveals a new mode of cancer dissemination. Large clusters of cancer epithelial cells displaying an inverted apico-basolateral polarity, which we term Tumour Spheres with Inverted Polarity (TSIPs), were observed throughout the process of tumour dissemination. We show that TSIPs form and propagate through the collective apical budding of hyper-methylated neoplastic tissues. Despite their inverted topology, TSIPs collectively invade extracellular matrices, paired patients¹ peritoneum explants and initiate metastases in mice xenograft models. Further, the presence of TSIPs in peritoneal effusions correlates with metastases burden and adverse patient prognosis. Thus, despite their having a robust epithelial architecture, TSIPs appear to drive the peritoneal dissemination of CRC, as well as other primary cancers, such as breast carcinoma. By applying cell biological methods to live primary cancer specimens, we provide an alternative conception of cancer dissemination that goes against the prevailing consensus and could not be anticipated from experimental model systems.
Department of Molecular and Translational Medicine, University of Brescia
"Stromal delivery of long Pentraxin-3 impairs FGF/FGFR-dependent tumor growth and metastasis"
The fibroblast growth factor (FGF)/FGF receptor (FGFR) system plays a crucial role in cancer by affecting tumor growth, angiogenesis, drug resistance and escape from anti-angiogenic anti-vascular endothelial growth factor therapy. The soluble pattern recognition receptor long-pentraxin 3 (PTX3) acts as a multi-FGF antagonist. In a recent study we demonstrated that local and systemic delivery of human PTX3 in transgenic mice driven by the endothelial specific Tie2 promoter inhibits tumor growth, angiogenesis and metastasis in heterotopic, orthotopic and autochthonous FGF-dependent tumor models. Moreover, NMR data and pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2 were used for the identification of the first small molecule chemical (NSC12) which acts as an orally active extracellular FGF trap with significant implications in cancer therapy. We are currently characterizing the role of PTX3 expression in different types of solid and hematological tumors.