Abstract

Melanoma cells frequently utilize bleb-driven amoeboid migration to navigate confined microenvironments during metastasis. Through a morphology-based drug repurposing screen, we identified the anti-migraine medication dihydroergotamine (DHE) as a potent inhibitor of this behavior. We show that DHE suppresses amoeboid motility by targeting serotonin receptors, primarily 5-HTR7. Trace levels of peripheral serotonin activates 5-HTR7, which in turn stimulates cAMP/PKA and ROCK signaling. This signaling cascade increases the cortical contractility necessary to sustain blebbing. Accordingly, DHE treatment or PKA inhibition significantly impairs confined migration without altering cell proliferation. Clinically, elevated levels of serotonin-degrading enzymes, such as MAOB, correlate with favorable patient prognoses and are reduced in metastatic lesions. Ultimately, these findings reveal an unanticipated role for peripheral serotonin in melanoma biomechanics and highlight serotonin receptors as highly actionable targets to limit metastatic dissemination.