Large Oncosome-Loaded VAPA Promotes Bone-Tropic Metastasis of Hepatocellular Carcinoma Via Formation of Osteoclastic Pre-Metastatic Niche,Advanced Science

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Large Oncosome-Loaded VAPA Promotes Bone-Tropic Metastasis of Hepatocellular Carcinoma Via Formation of Osteoclastic Pre-Metastatic Niche
Advanced Science ( IF 14.3 ) Pub Date : 2022-09-28 , DOI: 10.1002/advs.202201974
Shuxia Zhang _{1,

2} , Xinyi Liao _{1,

2} , Suwen Chen _{1,

2} , Wanying Qian _{1,

2} , Man Li _{1,

2} , Yingru Xu _{1,

2} , Meisongzhu Yang _{1,

2} , Xincheng Li _{1,

2} , Shuang Mo _{1,

2} , Miaoling Tang _{1,

2} , Xingui Wu _{1,

2} , Yameng Hu _{1,

2} , Ziwen Li _{1,

2} , Ruyuan Yu _{1,

2} , Ainiwaerjiang Abudourousuli _{1,

2} , Libing Song ₃ , Jun Li _{1,

2}

Affiliation

Tumor-derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre-metastatic niche that facilitates organotropic metastasis. Identifying the organ-specific molecular determinants of EVs can develop potential anti-metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer-derived EVs, are found to play a crucial role in facilitating bone-tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre-metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP-associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV-integrin. VAPA-enriched LOs-induced pre-metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs-delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott–Aldrich syndrome protein (N-WASP) via dual mechanisms, consequently resulting in ARP2/3 complex-mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N-WASP inhibitor 187-1-packaged LOs (LOs/187-1) dramatically abolishes the inductive effect of VAPA-enriched LOs on pre-metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone-tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis.

中文翻译：

负载大肿瘤的 VAPA 通过形成破骨细胞转移前微环境促进肝细胞癌的骨向性转移

肿瘤来源的细胞外囊泡（EV）在选择性调节远端器官的微环境中发挥关键介质的作用，以产生促进器官转移的转移前生态位。识别 EV 的器官特异性分子决定因素可以开发潜在的抗转移治疗靶点。在当前的研究中，发现大肿瘤体（LO），即非典型的大的癌症衍生的EV，通过设计破骨细胞转移前生态位并建立恶性细胞，在促进肝细胞癌细胞（HCC）细胞的骨向转移中发挥着至关重要的作用。破骨细胞和肝癌细胞之间的循环。跨膜蛋白 VAMP 相关蛋白 A (VAPA) 通过与 LO 标记α V 整合素直接相互作用而在 LO 表面显着富集。富含 VAPA 的 LO 诱导的转移前教育将骨骼转变为肥沃的环境，支持转移性 HCC 细胞的生长。从机械角度来看，LOs 递送的 VAPA 整合到破骨细胞的质膜上，通过双重机制直接与神经 Wiskott-Aldrich 综合征蛋白 (N-WASP) 相互作用并激活，从而导致破骨细胞和破骨细胞生成中 ARP2/3 复合物介导的肌动蛋白细胞骨架重组。重要的是，用 N-WASP 抑制剂 187-1 包装的 LO（LOs/187-1）治疗可显着消除富含 VAPA 的 LO 对转移前微环境形成的诱导作用，并阻止 HCC 骨转移。这些发现揭示了 HCC 骨向性的合理机制，并且可以代表预防 HCC 骨转移的潜在策略。

更新日期：2022-09-28

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