近日，美国得克萨斯大学西南医学中心Gaudenz Danuser等研究人员合作发现，小泡通过组装致癌信号中枢来促进细胞存活。相关论文于2023年3月1日在线发表在《自然》杂志上。
研究人员通过三维成像和对细胞形态状态的操纵表明，小泡形成触发了质膜近端信号枢纽的形成，从而赋予了失巢凋亡抵抗力。具体来说，在黑色素瘤细胞中，小泡产生了质膜轮廓，招募曲率感应隔蛋白作为构成性活性突变NRAS和效应物的支架。这些信号枢纽激活ERK和PI3K——成熟的促进生存途径的启动器。抑制小泡或隔蛋白对附着良好的细胞的生存没有什么影响，但在脱离的细胞中，它会导致NRAS错位，降低MAPK和PI3K活性，并最终导致死亡。这揭示了突变的NRAS作为有效的癌蛋白运作的形态学要求。
此外，尽管一些BRAF突变的黑色素瘤细胞在基底状态下不依赖这种生存途径，但BRAF和MEK的抑制使它们对小泡和隔蛋白的抑制都非常敏感。此外，为维持小泡形成而设计的成纤维细胞获得了与癌细胞相同的抗炎性，即使没有致癌突变。因此，小泡是强有力的信号细胞器，能够将众多的细胞信息流整合成协调一致的细胞反应，在这种情况下，赋予了强大的失巢凋亡抗性。
研究人员表示，大多数人类细胞需要锚定才能生存。细胞与基质的粘附激活了各种信号途径，如果没有这些信号途径，细胞就会发生失巢凋亡（anoikis）——一种程序性细胞死亡的形式。获得耐药性是癌症疾病进展的一个关键步骤，因为转移的细胞往往失去对周围组织的牢固附着。在这些附着力差的状态下，细胞采用圆形的形态，形成小的半球形质膜突起，称为小泡（bleb）。在变形虫迁移的背景下，已经对小泡的功能进行了彻底的研究，但在其他情况下，对它的研究却少得多。。
附：英文原文
Title: Blebs promote cell survival by assembling oncogenic signalling hubs
Author: Weems, Andrew D., Welf, Erik S., Driscoll, Meghan K., Zhou, Felix Y., Mazloom-Farsibaf, Hanieh, Chang, Bo-Jui, Murali, Vasanth S., Gihana, Gabriel M., Weiss, Byron G., Chi, Joseph, Rajendran, Divya, Dean, Kevin M., Fiolka, Reto, Danuser, Gaudenz
Issue&Volume: 2023-03-01
Abstract: 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 blebs4,5,6,7,8,9,10,11. 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.
DOI: 10.1038/s41586-023-05758-6
Source: https://www.nature.com/articles/s41586-023-05758-6
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
