Department of Biochemistry College of Medicine Soonchunhyang University Cheonan Chungcheongnam Republic of Korea.
Research Institute of the McGill University Health Centre Glen Site McGill University Montreal Quebec Canada.
J Extracell Vesicles. 2021 Jun;10(8):e12091. doi: 10.1002/jev2.12091. Epub 2021 Jun 10.
Oncogenic RAS impacts communication between cancer cells and their microenvironment, but it is unclear how this process influences cellular interactions with extracellular vesicles (EVs). This is important as intercellular EV trafficking plays a key role in cancer invasion and metastasis. Here we report that overexpression of mutant RAS drives the EV internalization switch from endocytosis (in non-transformed cells) to macropinocytosis (in cancer cells) resulting in enhanced EV uptake. This process depends on the surface proteoglycan, fibronectin and EV engulfment mechanism regulated by CRAF. Both mutant RAS and activated CRAF expression is associated with formation of membrane ruffles to which they colocalize along with actin, sodium-hydrogen exchangers (NHEs) and phosphorylated myosin phosphatase (pMYPT). RAS-transformed cells internalize EVs in the vicinity of ruffled structures followed by apparent trafficking to lysosome and degradation. NHE inhibitor (EIPA) suppresses RAS-driven EV uptake, along with adhesion-independent clonal growth and experimental metastasis in mice. Thus, EV uptake may represent a targetable step in progression of RAS-driven cancers.
致癌 RAS 会影响癌细胞与其微环境之间的通讯，但目前尚不清楚这一过程如何影响细胞与细胞外囊泡 (EV) 的相互作用。这一点很重要，因为细胞间 EV 转运在癌症侵袭和转移中起着关键作用。在这里，我们报告说，突变 RAS 的过表达会驱动 EV 内化开关从胞吞作用（在非转化细胞中）转变为巨胞饮作用（在癌细胞中），从而增强 EV 的摄取。这个过程依赖于表面蛋白聚糖、纤连蛋白和 CRAF 调节的 EV 吞噬机制。突变 RAS 和激活的 CRAF 的表达都与形成细胞膜皱襞有关，它们与肌动蛋白、钠离子-氢交换器 (NHEs) 和磷酸化肌球蛋白磷酸酶 (pMYPT) 共定位。RAS 转化的细胞在皱襞结构附近内化 EV，随后明显转运到溶酶体并降解。NHE 抑制剂 (EIPA) 可抑制 RAS 驱动的 EV 摄取，以及小鼠中不依赖黏附的克隆生长和实验性转移。因此，EV 的摄取可能是 RAS 驱动的癌症进展的一个可靶向步骤。
