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

Segal, D.; Wang, X.; Mazloom-Farsibaf, H.; Rajendran, D.; Butler, E.; Chen, B.; Chang, B.-J.; Ahuja, K.; Perny, A.; Bhatt, K.; Reed, D. K.; Castrillon, D.; Lee, J.; Jeffery, E.; Wang, L.; Williams, N. S.; Rajaram, S.; Fiolka, R. P.; Skapek, S. X.; Hon, G. C.; Amatruda, J.; Danuser, G.

doi:10.1101/2024.09.23.614468

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bioRxiv · 10.1101/2024.09.23.614468

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

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Abstract

Plasticity is a hallmark function of cancer cells, yet the mechanisms that enable dynamic switching between survival states remain incompletely understood. Here, we identify Caveolin-1, a membrane-domain scaffolding protein, as a context-dependent regulator of survival signaling in Ewing sarcoma (EwS). Single-cell analyses reveal a distinct subpopulation of EwS cells marked by high CD99 and elevated Caveolin-1 expression. These CD99High cells exhibit unique morphology, transcriptional programs, and markedly enhanced survival both under chemotherapeutic challenge and in vivo. Importantly, CD99High and CD99Low states are reversible, providing EwS cells with a flexible route to survival-oriented plasticity. Mechanistically, we show that Caveolin-1 in CD99High cells orchestrates PI3K/AKT survival signaling by modulating the spatial organization of PI3K activity on the plasma membrane. We propose that the CD99High state establishes a Caveolin-1-driven signaling architecture that supports survival through mechanisms distinct from those used by CD99Low cells. These findings uncover a dynamic state transition in EwS cells and position Caveolin-1 as a key driver of context-specific survival signaling.

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Segal, D., Wang, X., Mazloom-Farsibaf, H., Rajendran, D., Butler, E., Chen, B., Chang, B.-J., Ahuja, K., Perny, A., Bhatt, K., Reed, D. K., Castrillon, D., Lee, J., Jeffery, E., Wang, L., Williams, N. S., Rajaram, S., Fiolka, R. P., Skapek, S. X., Hon, G. C., Amatruda, J., Danuser, G.. 2024-09-25. Caveolin-1 regulates context-dependent signaling and survival in Ewing Sarcoma.. https://doi.org/10.1101/2024.09.23.614468

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