Tumour-derived exosomal piR-25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition
Tumour-derived exosomal piR-25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition
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肿瘤源性外泌体piR-25783通过诱导成纤维细胞向肌成纤维细胞转变促进卵巢癌网膜转移
DOI：
10.1038/s41388-022-02560-y
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发表时间：
2022-12-08
期刊：
影响因子：
8
通讯作者：
Wang，Zehua
中科院分区：
文献类型：
--
作者：
Li，Guoqing;Yi，Xiaoqing;Wang，Zehua
卵巢癌固有地对富含脂肪的大网膜具有明显的转移性器官嗜性，从而促进疾病进展。虽然转移前微环境（PMM）已被称为经常发挥促转移的作用，在这个过程中，不完全的机制洞察PMM形成阻止其治疗靶向。网膜成纤维细胞可以被肿瘤细胞激活以分化成肌成纤维细胞，称为成纤维细胞向肌成纤维细胞转化（FMT），这反过来又增强了癌症的侵袭性。在这里，我们报告了癌细胞和网膜成纤维细胞之间的串扰通过外泌体piR-25783，这燃料肿瘤转移。肿瘤细胞分泌的外泌体piR-25783激活成纤维细胞中的TGF-β/SMAD 2/SMAD 3途径，并促进网膜中的FMT，同时沿着各种细胞因子的分泌和增殖、迁移和侵袭特性的提高，从而有助于PMM的形成。此外，piR-25783诱导的肌成纤维细胞促进网膜中的肿瘤植入和生长。此外，卵巢癌中piR-25783的过表达与不利的临床病理特征和较短的生存期相关。在这项研究中，我们提供了分子，功能和翻译的证据表明，外泌体piR-25783在PMMs的形成和转移性疾病的发展中起着重要的作用，在体外和体内，并可能作为一个潜在的治疗靶点卵巢癌转移。
Ovarian carcinoma inherently possesses a distinct metastatic organotropism for the adipose-rich omentum, contributing to disease progression. Although the premetastatic microenvironment (PMM) has been known to often play a prometastatic role during the process, incomplete mechanistic insight into PMM formation has prevented its therapeutic targeting. Omental fibroblasts can be activated by tumour cells to differentiate into myofibroblasts, termed the fibroblast-to-myofibroblast transition (FMT), which, in turn, enhances cancer aggressiveness. Here, we report crosstalk between cancer cells and omental fibroblasts through exosomal piR-25783, which fuels tumour metastasis. Tumour cell-secreted exosomal piR-25783 activates the TGF-β/SMAD2/SMAD3 pathway in fibroblasts and promotes the FMT in the omentum along with the secretion of various cytokines and elevation of proliferative, migratory, and invasive properties, contributing to the formation of PMMs. Furthermore, piR-25783-induced myofibroblasts promote tumour implantation and growth in the omentum. In addition, the overexpression of piR-25783 in ovarian carcinoma is associated with unfavourable clinicopathological characteristics and shorter survival. In this study, we provide molecular, functional, and translational evidence suggesting that exosomal piR-25783 plays an important role in the formation of PMMs and the development of metastatic diseases in vitro and in vivo and may serve as a potential therapeutic target for ovarian carcinoma with metastasis.