Caveolin-1 regulates context-dependent signaling and survival in Ewing Sarcoma

Cellular plasticity is a hallmark function of cancer, but many of the underlying mechanisms are not well understood. We uncover Caveolin-1, a scaffolding protein that modulates plasma membrane domain organization, as a context-specific regulator of survival signaling in Ewing sarcoma (EwS). Single cell analysis reveals a distinct subpopulation of EwS cells, which highly express the cell surface marker CD99 as well as Caveolin-1. CD99 High cells isolated through flow cytometry differ from CD99 Low cells in morphology, gene expression, and survival capabilities in vivo. Our work demonstrates that elevated Caveolin-1 expression in these cells plays a key role in the regulation of PI3K/AKT survival signaling, through subcellular organization of PI3K activity at the cell surface. We thus propose a model where the CD99 High state develops a Cav-1 controlled signaling network to regulate cell survival that is distinct from the AKT-agnostic survival of CD99 Low cells. Overall, this work identifies a state transition of EwS cells and uncovers Caveolin-1 as a driver of survival signaling in a context-dependent manner.