Tumor exosomes induce tunneling nanotubes in lipid raft-enriched regions

of human mesothelioma cells

Venugopal Thayanithya, Victor Babatundeb, Elizabeth L. Dicksonc, Philip Wonga, Sanghoon Ohd, Xu Ked, Afsar Barlasd, Sho Fujisawad, Yevgeniy Romind, André L.

Moreirae, Robert J. Downeyf, Clifford J. Steerg, Subbaya Subramanianh, Katia Manova-Todorovad, Malcolm A.S. Mooreb, Emil Loua

From The University of Minnesota and

Memorial Sloan-Kettering Cancer Center

Experimental Cell Research, http://dx.doi.org/10.1016/j.yexcr.2014.01.014

Introduction

• Tunneling nanotubes (TnTs) are long, non-adherent, actin-based cellular extensions that act as open conduits for transport of cellular cargo between connected cells.

• Exosomes are also being studied for their role in intercellular communication.

• Associations or relationships between TnTs and exosomes are unknown.

• In the present study, we explored exosomes as potential mediators of TnT formation in mesothelioma, and also the potential relationship of lipid rafts to TnT formation.

Highlights and Conclusions

• Exosomes derived from malignant cells can stimulate an increased rate in the formation of tunneling nanotubes, which in turn can serve as a conduit for intercellular transfer of these exosomes.

• Most notably, exosomes derived from benign mesothelial cells had no effect on nanotube formation.

• Cells forming nanotubes were enriched in lipid rafts at a greater number compared with cells not forming nanotubes.

• Our findings provide the first evidence to date of causal and potentially synergistic association of exosomes and tunneling nanotubes in cancer.

Other pertinent work on TnTs from our group

• E Lou, S Fujisawa, A Morozov, A Barlas, Y Romin, Y Dogan, AL Moreira, K Manova-Todorova, MAS Moore. Tunneling Nanotubes Provide a Unique Conduit for Intercellular Transfer of Cellular Contents in Human Malignant Pleural Mesothelioma. PLoS ONE 7(3):e33093. Epub 2012 Mar 9.

• E Lou, S Fujisawa, A Barlas, Y Romin, K Manova-Todorova, M.A.S. Moore, S Subramanian. Tunneling Nanotubes: A new paradigm for studying intercellular communication and therapeutics in cancer. Communicative & Integrative Biology 5(4): 399-403, July 2012. doi: 10.4161/cib.20569.

• E Lou, S Subramanian, CJ Steer. Pancreatic Cancer: Modulation of KRAS,

MicroRNAs and Intercellular Communication in the Setting of Tumor Heterogeneity. Pancreas 42(8):1218-26, 2013.

• Our Lab webpage: http://www.dom.umn.edu/hematology-oncology-and-transplantation/faculty/emil-lou/lou-lab/index.htm