Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype.

Yamicia Connor,Elazer R Edelman,Bruce Zetter,Yonatan Tekleab,Ashish Kulkarni,Harold Dvorak,Or Gadish,Seema Sehrawat,Amjad Husain,Venkata Sabbisetti,Shiladitya Sengupta,Shelly Kaushik,Cherelle Walls,Sarah Tekleab,Shyama Nandakumar

doi:10.1038/ncomms9671

Abstract

Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of ‘metastatic hijack': cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in vivo. Targeting these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.

Highlights

Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer
The cancer cells preferentially attached to the vascular network, acquired an elongated phenotype and invaginated into the endothelial network (Fig. 1a). This was in contrast to the phenotype reported earlier, where monocultures of breast cancer cells were typically found to form characteristic mammospheres on 3D matrices (Fig. 1b)[29]. These results indicated that the interactions between metastatic cancer cells and endothelial cells can create a ‘niche’ that facilitates an invasive phenotype in the cancer cells
Previous studies have shown that the endothelial tubules formed in these studies represent an ‘inside-out’ model of a blood vessel[30], indicating that the cancer cells are exposed to the thrombogenic apical side of an endothelial cell, that is, the current assay likely modelled cancer cell–endothelium interactions in the context of extravasation

Summary

Introduction

Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. We report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. In a recent study, communication between cancer and endothelial cells through tumour-secreted microRNAs (miRNAs) packaged in microvesicles was implicated in angiogenesis. Antagomirs that target this miRNA-mediated signalling were shown to inhibit angiogenesis and reduce tumour burden[11]. Whether similar intercellular nanostructure-mediated communication can be harnessed by cancer cells to modulate the endothelium is not known

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