大多数人类细胞需要锚定才能存活。细胞与基质附着激活多样的信号通路，如果没有这些通路，细胞会经历一种编程性细胞死亡形式，即离基死亡。获得离基抵抗力是癌症疾病进展的关键步骤，因为转移的细胞通常失去与周围组织的坚固附着。在这些附着不良的状态下，细胞采用球形形态并形成称为泡的小半球形质膜突起。在变形虫运动的背景下，泡的功能已经得到了深入研究，但在其他情况下很少被研究。在这里，我们通过三维成像和细胞形态状态的操作，展示泡触发靠近质膜的信号中心的形成，赋予细胞离基抗性。特别是在黑色素瘤细胞中，泡产生了质膜轮廓，招募了曲率敏感的丝环蛋白蛋白作为构成性活跃突变 NRAS 和效应因子的支架。这些信号中心激活 ERK 和 PI3K，这些是促进细胞存活的路径。抑制泡或丝环蛋白对于附着良好的细胞的生存几乎没有影响，但对于脱落的细胞，它会导致 NRAS 定位错误，减少 MAPK 和 PI3K 活性，并最终导致细胞死亡。这揭示了突变 NRAS 作为有效的癌基因蛋白质的形态学要求。此外，一些 BRAF 基因突变的黑色素瘤细胞在基础状态下不依赖于这条生存途径，但是抑制 BRAF 和 MEK 对泡和丝环蛋白的抑制都具有强烈的敏感性。此外，工程化的成纤维细胞可持续出现泡膜，即使没有携带致癌基因突变也会获得相同的离基抗性。因此，泡是能够将无数细胞信息流整合成有力细胞响应的强大信号质体。在这种情况下，赋予了有力的离基抗性。©2023年作者，独家许可Springer Nature Limited。

Most human cells require anchorage for survival. Cell-substrate adhesion activates diverse signalling pathways, without which cells undergo anoikis-a form of programmed cell death1. Acquisition of anoikis resistance is a pivotal step in cancer disease progression, as metastasizing cells often lose firm attachment to surrounding tissue2,3. In these poorly attached states, cells adopt rounded morphologies and form small hemispherical plasma membrane protrusions called blebs4-11. Bleb function has been thoroughly investigated in the context of amoeboid migration, but it has been examined far less in other scenarios12. Here we show by three-dimensional imaging and manipulation of cell morphological states that blebbing triggers the formation of plasma membrane-proximal signalling hubs that confer anoikis resistance. Specifically, in melanoma cells, blebbing generates plasma membrane contours that recruit curvature-sensing septin proteins as scaffolds for constitutively active mutant NRAS and effectors. These signalling hubs activate ERK and PI3K-well-established promoters of pro-survival pathways. Inhibition of blebs or septins has little effect on the survival of well-adhered cells, but in detached cells it causes NRAS mislocalization, reduced MAPK and PI3K activity, and ultimately, death. This unveils a morphological requirement for mutant NRAS to operate as an effective oncoprotein. Furthermore, whereas some BRAF-mutated melanoma cells do not rely on this survival pathway in a basal state, inhibition of BRAF and MEK strongly sensitizes them to both bleb and septin inhibition. Moreover, fibroblasts engineered to sustain blebbing acquire the same anoikis resistance as cancer cells even without harbouring oncogenic mutations. Thus, blebs are potent signalling organelles capable of integrating myriad cellular information flows into concerted cellular responses, in this case granting robust anoikis resistance.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.