Final Report Summary - FP7 TNT FUNCTION (Towards the mechanism and function of tunneling nanotube (TNT)-dependent, intercellular exchange of cargo)
Development and maintenance of multicellular organisms rely largely on the ability of cells to communicate with each other. Aberrations in the systems of communication can provoke deep functional deregulations and lead to diseases. A striking example is the complex communication between cancer cells and normal cells that are present in the microenvironment (stroma cells) which undergo profound modifications and promote cancer progression and invasion. Cells use a variety of distinct structures to communicate with each other. Some cellular communication processes are based on direct cell-cell contacts that mediate the local spread of informations, among them the chemical and immune synapses, GAP junction channels and tunnelling nanotubes (TNTs). TNTs mediate both short and long range communication through thin membranous bridges connecting cells. The laboratory has discovered TNTs in 2004 and since then several studies have demonstrated the importance of TNTs in a broad range of processes involved in cellular and developmental biology, immunity, viral spread or even drugs resistance of cancer cells. A growing number of cargos are found in TNT including endocytic organelles, proteins such as prion, RNAs, miRNAs, mitochondria and even viruses.
The aim of the study was to generate the missing basic knowledge allowing us to understand the function of TNTs and the mechanism underlying the transfer. During two years, extensive efforts were put to challenge three main questions:
(i) which cellular compartment(s) is (are) transferred;
(ii) what is the molecular mechanism involved in the transfer and
(iii) what are the cargoes transferred.
By looking at the well-known protein markers from different subtypes of cellular compartments, we find a particular, specific subclass of vesicles that are present in cells and are transferred to their neighbors. The transfer from one cell to another is mediated by nanotubes and we found the key actors that regulate this pathway. In addition, we identified a major cargo that is transported, and that this transport occurs specifically in cancer cells and from cancer cells to the normal cells surrounding them. The results of this study are expected to strongly impact broad research fields such as cell biology and cancer biology. The transport of protein receptor from tumour cells to fibroblasts is a pioneer finding which shall be taken in consideration in cancer-stroma studies and in particular in anti-cancer therapeutic strategies that target the receptor and which are currently under clinical trials. In addition, an innovant experimental approach was invented to detect the transfer of the protein receptor in a mouse model in vivo, opening the way for many clinical applications, such as the test of new drugs that target cancer-stroma communication, a driving force for cancer progression and yet poorly targeted by available treatments.