Endothelial Calcium Firing Mediates the Extravasation of Metastatic Tumor Cells

Overview

Journal iScience

Publisher Cell Press

Date 2025 Feb 3

PMID 39898056

Authors

Marina Peralta

Amandine Dupas

Annabel Larnicol

Olivier Lefebvre

Ruchi Goswami

Tristan Stemmelen

Anne Molitor

Raphael Carapito

Salvatore Girardo

Nael Osmani

Jacky G Goetz

Affiliations

Soon will be listed here.

Abstract

Metastatic dissemination is driven by genetic, biochemical, and biophysical cues that favor the distant colonization of organs and the formation of life-threatening secondary tumors. We have previously demonstrated that endothelial cells (ECs) actively remodel during extravasation by enwrapping arrested tumor cells (TCs) and extruding them from the vascular lumen while maintaining perfusion. In this work, we dissect the cellular and molecular mechanisms driving endothelial remodeling. Using high-resolution intravital imaging in zebrafish embryos, we demonstrate that the actomyosin network of ECs controls tissue remodeling and subsequent TC extravasation. Furthermore, we uncovered that this cytoskeletal remodeling is driven by altered endothelial-calcium (Ca) signaling caused by arrested TCs. Accordingly, we demonstrated that the inhibition of voltage-dependent calcium L-type channels impairs extravasation. Lastly, we identified P2X4, TRP, and Piezo1 mechano-gated Ca channels as key mediators of the process. These results further highlight the central role of endothelial remodeling during the extravasation of TCs and open avenues for successful therapeutic targeting.

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