Oncogenic RAS drives the CRAF-dependent extracellular vesicle uptake mechanism coupled with metastasis.
Oncogenic RAS drives the CRAF-dependent extracellular vesicle uptake mechanism coupled with metastasis.
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DOI：
10.1002/jev2.12091
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发表时间：
2021-06
影响因子：
16
通讯作者：
Rak J
中科院分区：
文献类型：
--
作者：
Choi D;Montermini L;Meehan B;Lazaris A;Metrakos P;Rak J
致癌RAS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小泡(EVS)的相互作用。这一点很重要，因为细胞间的EV运输在癌症的侵袭和转移中起着关键作用。在这里，我们报告了突变RAS的过表达驱动EV内化从内吞(在未转化的细胞中)转变为大吞饮(在癌细胞中)，从而导致EV摄取的增强。这一过程依赖于CRAF调节的表面蛋白多糖、纤维连接蛋白和EV吞噬机制。突变的RAS和激活的CRAF表达都与膜褶皱的形成有关，它们与肌动蛋白、钠氢交换器(NHEs)和磷酸化肌球蛋白磷酸酶(PMYPT)共同定位于膜褶皱上。RAS转化的细胞在褶皱的结构附近内化EV，随后明显地运输到溶酶体和降解。NHE抑制剂(EIPA)抑制RAS驱动的EV摄取，并抑制小鼠的黏附非依赖性克隆生长和实验性转移。因此，EV摄取可能是RAS驱动的癌症进展中的一个有针对性的步骤。
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.
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
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通讯作者：
Edinger AL
影响因子：
3.7
作者：
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通讯作者：
QUARONI, A