PO.TB10.15 · 肿瘤生物学
癌症相关成纤维细胞来源的细胞外囊泡中的 ATP6V1C1 影响肺腺癌的转移和治疗敏感性
ATP6V1C1 in cancer-associated fibroblast-derived extracellular vesicles affects the metastasis and therapeutic sensitivity of lung adenocarcinoma
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摘要 Abstract
中文摘要
已知癌症相关成纤维细胞（CAF）来源的细胞外囊泡（EV）可促进肺腺癌（LUAD）进展，但介导这一作用的特定蛋白货物仍未明确界定。在本研究中，我们从配对的 LUAD 肿瘤和邻近非癌组织中建立了一个患者来源成纤维细胞（PDF）文库。通过整合转录组分析和表面标志物鉴定，我们对 CAF 和正常成纤维细胞（NF）进行了表征，随后使用 transwell 实验分离出一个具有高促迁移活性的独特 CAF 亚群。对来自 30 对匹配 CAF-NF 的 EV 进行的定量蛋白质组学分析揭示了一个包含 2,492 种蛋白质的高质量数据集，并鉴定出 ATP6V1C1（V-ATPase 复合物的一个亚基）为促迁移 CAF-EV 中高度富集的蛋白质。我们进一步证明，CAF-EV 介导的 ATP6V1C1 转移驱动了 LUAD 细胞的迁移和转移，这一发现在细胞系、患者来源细胞（PDC）以及原位患者来源异种移植（PDX）模型中得到了有力验证。在分子层面上，EV 递送的 ATP6V1C1 通过下调转录因子 ID1 抑制了胰岛素样生长因子结合蛋白 3（IGFBP3）。这种对 IGFBP3 的抑制不仅触发了上皮-间充质转化（EMT），还放大了由 CAF 分泌的 IGF1 驱动的 IGF1/IGF1R/Akt/ERK 致癌通路。这种双重作用形成了一个自我强化的前馈环路，加剧了转移。使用 PDC 和患者来源类器官（PDO）进行的高通量筛选鉴定出决奈达隆（dronedarone）为一种有前景的药物再利用候选药物；其治疗效果与 ATP6V1C1 表达呈负相关。靶向 ATP6V1C1 破坏了胆固醇稳态，并与决奈达隆协同作用，在临床前模型中克服了对 EGFR 酪氨酸激酶抑制剂（EGFR-TKI）的耐药性。总之，我们的研究结果揭示了 ATP6V1C1 作为 LUAD 转移的双重调控因子，并提出了一种新型的靶向基质的联合疗法，以抑制肿瘤进展并对抗耐药性。
查看英文原文 English abstract
Cancer-associated fibroblast (CAF)-derived extracellular vesicles (EVs) are known to promote lung adenocarcinoma (LUAD) progression, yet the specific protein cargos responsible for this effect remain poorly defined. In this study, we generated a library of patient-derived fibroblasts (PDFs) from paired LUAD tumor and adjacent noncancerous tissues. Through integrated transcriptomic analysis and surface marker identification, we characterized CAFs and normal fibroblasts (NFs), subsequently isolating a distinct CAF subset with high pro-migratory activity using transwell assays. Quantitative proteomic profiling of EVs from 30 matched CAF-NF pairs revealed a high-quality dataset of 2,492 proteins and identified ATP6V1C1, a subunit of the V-ATPase complex, as a highly enriched protein in pro-migratory CAF-EVs. We further demonstrated that CAF-EV-mediated transfer of ATP6V1C1 drove LUAD cell migration and metastasis, a finding robustly validated in cell lines, patient-derived cells (PDCs), and an orthotopic patient-derived xenograft (PDX) model. At the molecular level, EV-delivered ATP6V1C1 suppressed insulin-like growth factor binding protein 3 (IGFBP3) by downregulating the transcription factor ID1. This suppression of IGFBP3 not only triggered epithelial-mesenchymal transition (EMT) but also amplified the IGF1/IGF1R/Akt/ERK oncogenic pathway driven by CAF-secreted IGF1. This dual action creates a self-reinforcing feed-forward loop that exacerbates metastasis. A high-throughput screen using PDCs and patient-derived organoids (PDOs) identified dronedarone as a promising drug repurposing candidate; its therapeutic efficacy was inversely correlated with ATP6V1C1 expression. Targeting ATP6V1C1 disrupted cholesterol homeostasis and synergized with dronedarone to overcome resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in preclinical models. In conclusion, our findings unveil ATP6V1C1 as a dual regulator of LUAD metastasis and propose a novel stroma-targeted combination therapy to suppress tumor progression and combat drug resistance.
利益披露 Disclosure
X. Chen, None..
J. Li, None..
K. Xiao, None.