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

Plasticity is a hallmark function of cancer cells, but many of the underlying mechanisms have yet to be discovered. In this study, we identify Caveolin-1, a scaffolding protein that organizes plasma membrane domains, as a context-dependent regulator of survival signaling in Ewing sarcoma (EwS). Single cell analyses reveal a distinct subpopulation of EwS cells, which highly express the surface marker CD99 as well as Caveolin-1. CD99 High cells exhibit distinct morphology, gene expression, and enhanced survival capabilities compared to CD99 Low cells, both under chemotherapeutic challenge and in vivo. Mechanistically, we show that elevated Caveolin-1 expression in CD99 High cells orchestrates PI3K/AKT survival signaling by modulating the spatial organization of PI3K activity at the cell surface. Notably, CD99 itself is not directly involved in this pathway, making it a useful independent marker for identifying these subpopulations. We propose a model where the CD99 High state establishes a Cav-1-driven signaling network to support cell survival that is distinct from the survival mechanisms of CD99 Low cells. This work reveals a dynamic state transition in EwS cells and highlights Caveolin-1 as a key driver of context-specific survival signaling.