MERTK and RAC1P29S Drive Melanoma Cannibalism of T cells

Abstract

Metastatic melanoma cells are cannibalistic, engulfing living and dead lymphocytes, but the molecular mechanisms that drive this behavior, including how they recognize their targets, are unknown. RAC is a Rho family GTPase that plays a key role in F-actin dynamics. RAC1P29S is a hyperactivating driver mutation that is common in melanoma where it promotes proliferation, motility, and therapy-resistance. Here we show that RAC1P29S melanoma cells engulf more Jurkat T cells than an isogenic RAC1WT revertant line. Live imaging captured lamellipodial dynamics and whole-cell engulfment in real time. An inhibitor screen across RAC1P29S and RAC1WT patient-derived lines showed that cannibalism requires the phosphatidylserine receptor MERTK. A RAC1P29S line lacking detectable MERTK was not cannibalistic, indicating that RAC1 hyperactivity amplifies a specific, receptor-mediated response. RAC1P29S lines are sensitive to RAC and Arp2/3 inhibition. We propose a "grip and gulp" model in which MERTK provides the grip and Arp2/3-driven branched actin the gulp.