Imaging Tunneling Membrane Tubes Elucidates Cell Communication in Tumors

Intercellular communication is a vital yet underdeveloped aspect of cancer pathobiology. This Opinion article reviews the importance and challenges of microscopic imaging of tunneling nanotubes (TNTs) in the complex tumor microenvironment. The use of advanced microscopy to characterize TNTs in vitro and ex vivo, and related extensions called tumor microtubes (TMs) reported in gliomas in vivo, has propelled this field forward. This topic is important because the identification of TNTs and TMs fills the gap in our knowledge of how cancer cells communicate at long range in vivo, inducing intratumor heterogeneity and resistance to treatment. Here we discuss the concept that TNTs/TMs fill an important niche in the ever-changing microenvironment and the role of advanced microscopic imaging to elucidate that niche. Direct cell-to-cell communication between cellular conduits called tunneling nanotubes (TNTs) and tumor microtubes (TMs) is an emerging and novel concept in cancer cell biology. Over the past decade, the field has moved from studies in vitro to the examination of tumors ex vivo and, more recently, in vivo studies in animal models. Advanced microscopy techniques, including but not limited to confocal imaging, electron microscopy, stimulated emission depletion microscopy, and in vivo laser scanning microscopy, are being harnessed to better characterize the structure of TNTs and TMs at high resolution. More studies are needed to identify the function and mechanisms of TNTs and to determine the extent to which there is heterogeneity between different cell types.