Interactions via tunneling nanotubes and transfer of mitochondria between mesenchymal stem cells and target cancer cells - Effects on metabolism and biological function
Nakhle J.1, Gerbal-Chaloin S1, Daujat-Chavanieu M1, Hugnot JP.2, Charlot B.3 and Vignais ML.1
1IRMB, INSERM; 2INM, INSERM; 3IES, CNRS. 1,2,3 Univ Montpellier, Montpellier, France
Mesenchymal stem cells (MSCs) can form connections via tunneling nanotubes (TNTs) and transfer mitochondria to target cells, including cancer cells (Vignais et al., Stem Cells International, 2017). TNTs are thin membrane channels (less than 1 m in diameter) that allow long distance (over 100 m) intercellular connections. TNT-mediated MSC mitochondria transfers were observed both in vitro and in vivo. They lead to changes in the metabolism and functional properties of the target cells.
We designed a protocol - Mitoception - to transfer mitochondria isolated from MSCs to target cells, allowing testing of their biological effects. Applying this protocol to the breast cancer cell line MDA-MB-231, we showed that the acquisition of MSC mitochondria enhances their OXPHOS while it decreases their glycolysis activity. It also leads to increased MDA-MB-231 invasion and proliferation rates (Caicedo et al., Sci Rep., 2015).
Glioblastomas (GBM) are aggressive brain tumors treated, after resection, by concomitant radiotherapy and temozolomide chemotherapy. However, relapses occur notably due to glioblastoma cancer stem cells (GSCs) within the tumor. MSCs recruited to tumors have been shown to be involved in tumor progression and response to therapy in various types of cancer. The actual recruitment of human MSCs by glioblastoma was recently demonstrated, in mouse xenograft models of human glioblastoma.
We showed that human MSCs and GSCs form nanotubes in co-culture which leads to the transfer of mitochondria between these cells. We adapted our Mitoception technique to the glioblastoma stem cells (Nzigou Mombo et al., J. Vis. Exp., 2017), thus allowing testing of the effects of MSC mitochondria on GSC metabolism and resistance to therapy. We are also developing two chamber-microfluidic circuits to observe the formation of the TNTs and the mitochondria trafficking between MSCs and GSCs in the microcircuit microchannels, for further biophysical modeling of the mitochondria transport dynamics.
Supported by the Ligue Contre le Cancer-Comité de l'Aude (grant RAB17010FFA) (France)