SLC7A11 protects amoeboid-disseminating cancer cells from oxidative stress

Oxidative stress limits metastasis, and amoeboid cancer cells have been identified in a variety of cancers as a subset of metastatic cancer cells characterized by high Rho-ROCK-driven Myosin II activity. They display fast individual migration and have increased survival abilities during metastasis. Amoeboid migrating cells require lower mitochondrial metabolism, but how they maintain low oxidative stress remains unclear. Using a combination of cancer cell lines in complex matrices, mouse xenografts, patient databases, and tissue microarrays, we show that SLC7A11 is highly expressed in amoeboid cancer cells, at the invasive front of primary tumors, and in metastatic lesions. We find that high SLC7A11 expression supports cancer cell survival and 3D invasion by promoting Myosin II activity while protecting cancer cells against oxidative stress. Targeting SLC7A11 effectively impairs amoeboid behavior, highlighting its potential as a therapeutic vulnerability in metastatic melanomas.