应激诱导的Rab11a-外泌体在结直肠癌中诱导安非他酮介导的西妥昔单抗抗性。

IF 15.5 1区 医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-06-18 DOI:10.1002/jev2.12465
John D. Mason, Ewan Marks, Shih-Jung Fan, Kristie McCormick, Clive Wilson, Adrian L. Harris, Freddie C. Hamdy, Chris Cunningham, Deborah C. I. Goberdhan
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引用次数: 0

摘要

外泌体是内泌体系统在细胞内产生的分泌囊泡。我们之前已经证明,外泌体不仅在晚期内体中产生,也在以单体G蛋白Rab11a为标志的回收内体中产生。这些被称为 Rab11a-外泌体的囊泡在营养压力下优先从几种癌细胞类型中分泌出来,包括 HCT116 大肠癌(CRC)细胞。HCT116 Rab11a-外泌体具有特别强的信号活性,其中一些信号活性是由表皮生长因子受体(EGFR)配体安非拉酮(AREG)介导的。KRAS 是表皮生长因子受体(EGFR)的下游靶标,在晚期 CRC 中经常发现 KRAS 的突变激活形式。如果不存在这种情况,就可以使用西妥昔单抗等单克隆抗体来靶向表皮生长因子受体并阻断表皮生长因子受体配体(如 AREG)的作用。然而,患者不可避免地会对西妥昔单抗产生耐药性,这可能是由于获得了 KRAS 突变,也可能是由于非遗传性的微环境变化。在这里,我们展示了几种 CRC 细胞系中的营养应激会导致携带 AREG 的 Rab11a- 外泌体释放。我们证明,虽然可溶性 AREG 没有影响,但与来自西妥昔单抗抗性 KRAS 突变 HCT116 细胞的 Rab11a- 外泌体结合的 AREG 水平低得多,可以抑制西妥昔单抗对 KRAS 野生型 Caco-2 CRC 细胞的影响。通过使用中和性抗 AREG 抗体和细胞内表皮生长因子受体激酶抑制剂,我们发现这种效应是通过 AREG 激活表皮生长因子受体而不是活化的 KRAS 转移来介导的。因此,AREG在Rab11a-外泌体上的呈现会影响其与西妥昔单抗竞争的能力。我们认为,Rab11a-外泌体介导的这一机制有助于西妥昔单抗敏感细胞耐药性的建立,也可以解释为什么西妥昔单抗耐药肿瘤中只有部分细胞携带突变型 KRAS。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer

Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.

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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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