Segal Dagan, Wang Xiaoyu, Mazloom-Farisbaf Hanieh, Rajendran Divya, Butler Erin, Chen Bingying, Chang Bo-Jui, Ahuja Khushi, Perny Averi, Bhatt Kushal, Reed Dana Kim, Castrillon Diego H, Lee Jeon, Jeffery Elise, Wang Lei, Nguyen Khai, Williams Noelle S, Skapek Stephen X, Rajaram Satwik, Fiolka Reto, Jaqaman Khuloud, Hon Gary, Amatruda James F, Danuser Gaudenz
Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX.
Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX.
bioRxiv. 2025 Jan 28:2024.09.23.614468. doi: 10.1101/2024.09.23.614468.
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. cells exhibit distinct morphology, gene expression, and enhanced survival capabilities compared to cells, both under chemotherapeutic challenge and Mechanistically, we show that elevated Caveolin-1 expression in 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 state establishes a Cav-1-driven signaling network to support cell survival that is distinct from the survival mechanisms of cells. This work reveals a dynamic state transition in EwS cells and highlights Caveolin-1 as a key driver of context-specific survival signaling.
可塑性是癌细胞的一个标志性功能，但许多潜在机制尚未被发现。在本研究中，我们确定了小窝蛋白-1（一种组织质膜结构域的支架蛋白）是尤因肉瘤（EwS）中生存信号的上下文依赖性调节因子。单细胞分析揭示了EwS细胞的一个独特亚群，其高表达表面标志物CD99以及小窝蛋白-1。与其他细胞相比，这些细胞在化疗挑战和其他条件下均表现出独特的形态、基因表达和增强的生存能力。从机制上讲，我们表明这些细胞中小窝蛋白-1表达的升高通过调节细胞表面PI3K活性的空间组织来协调PI3K/AKT生存信号。值得注意的是，CD99本身并不直接参与该途径，使其成为识别这些亚群的有用独立标志物。我们提出了一个模型，其中该状态建立了一个由Cav-1驱动的信号网络来支持细胞生存，这与其他细胞的生存机制不同。这项工作揭示了EwS细胞中的动态状态转变，并突出了小窝蛋白-1作为上下文特异性生存信号的关键驱动因素。
