Balance of Mechanical Forces Drives Endothelial Gap Formation and May Facilitate Cancer and Immune-Cell Extravasation

TL;DR

This study presents a multiscale model showing that mechanical forces cause spontaneous endothelial gaps, which facilitate cancer and immune cell extravasation, with experimental validation indicating cells exploit these gaps for transmigration.

Contribution

The paper introduces a stochastic-mechanical multiscale model of endothelial gaps and demonstrates their spontaneous formation and role in cell extravasation, validated by experiments.

Findings

Gaps form spontaneously at endothelial vertices due to mechanical forces.

Cancer cells preferentially extravasate at vertices, exploiting gaps.

Experimental validation confirms model predictions.

Abstract

The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolayer and show that the dynamic nature of the endothelium leads to spontaneous gap formation, even without intervention from the transmigrating cells. These gaps preferentially appear at the vertices between three endothelial cells, as opposed to the border between two cells. We quantify the frequency and lifetime of these gaps, and validate our predictions experimentally. Interestingly, we find experimentally that cancer cells also preferentially extravasate at vertices, even when they first arrest on borders. This suggests that extravasating cells, rather than initially signaling to the endothelium, might exploit the autonomously forming gaps in the endothelium to initiate transmigration.