A mathematical model of tumor-endothelial interactions in a 3D co-culture.

Intravasation and extravasation of cancer cells through blood/lymph vessel endothelium are essential steps during metastasis. Successful invasion requires coordinated tumor-endothelial crosstalk, utilizing mechanochemical signaling to direct cytoskeletal rearrangement for transmigration of cancer cells. However, mechanisms underlying physical interactions are difficult to observe due to the lack of experimental models easily combined with theoretical models that better elucidate these pathways. We have previously demonstrated that an engineered 3D in vitro endothelial-epithelial co-culture system can be used to isolate both molecular and physical tumor-endothelial interactions in a platform that is easily modeled, quantified, and probed for experimental investigation. Using this platform with mathematical modeling, we show that breast metastatic cells display unique behavior with the endothelium, exhibiting a 3.2-fold increase in interaction with the endothelium and a 61-fold increase in elongation compared to normal breast epithelial cells. Our mathematical model suggests energetic favorability for cellular deformation prior to breeching endothelial junctions, expending less energy as compared to undeformed cells, which is consistent with the observed phenotype. Finally, we show experimentally that pharmacological inhibition of the cytoskeleton can disrupt the elongatation and alignment of metastatic cells with endothelial tubes, reverting to a less invasive phenotype.

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

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.