Bleb-based extravasation: conserved morphodynamics, divergent calcium control

Extravasation, the exit of cells from blood vessels, is essential in both development and disease, from germ cell migration to cancer metastasis. We show that all extravasating cells examined, avian primordial germ cells and diverse human cancer lines, form Ca{superscript 2}-dependent membrane blebs during transendothelial migration. Yet the source of Ca{superscript 2} diverges by lineage. PGCs and HT-1080 fibrosarcoma cells rely on store-operated Ca{superscript 2} entry (SOCE), whereas epithelial cancer cells such as PC-3 and MDA-MB-231 use IPR-mediated Ca{superscript 2} release from the endoplasmic reticulum. These findings establish bleb-based extravasation as a conserved morphodynamic strategy powered by distinct regulatory modules. Evolutionarily, they map onto an ancestral ER-release pathway and a metazoan-derived SOCE pathway. Conceptually, cancer blebbing emerges as a composite strategy that reactivates both ancient survival programs and developmental toolkits to maximize invasive success. This unified framework highlights Ca{superscript 2} supply as a critical bottleneck of vascular escape, offering new angles for targeting metastatic dissemination.