TAM衍生的EV中的CAV1-DOT1L轴协调VM并使PDAC对VM和VEGF的联合靶向敏感
CAV1-DOT1L axis in TAM-derived EVs orchestrates VM and sensitises PDAC to combined VM and VEGF targeting.
摘要(中文译文)
血管生成拟态（VM）是一种非内皮性血管化程序，维持胰腺导管腺癌（PDAC）的灌注和转移，但其调控因子和治疗脆弱性仍不清楚。为阐明调控VM的免疫和表观遗传机制，并确定克服VM驱动的PDAC进展的策略。研究结合了组织病理学、三维组织透明化、空间转录组学和单细胞RNA测序来绘制VM分布及其免疫微环境。采用组织微阵列、共培养实验和异种移植模型评估肿瘤相关巨噬细胞（TAM）的贡献。细胞外囊泡（EV）蛋白质组学和机制研究鉴定了货物分子和信号通路。使用DOT1L（端粒沉默干扰因子1样）抑制剂EPZ-5676和血管内皮生长因子受体（VEGFR）抑制剂阿昔替尼进行治疗验证。VM在PDAC中大量存在，随肿瘤分期增加而增多，且优先被TAM包围。M2样TAM促进管腔形成、侵袭和肿瘤生长，而阻断TAM来源的EV可消除这些效应。EV蛋白质组学鉴定出小窝蛋白-1（CAV1）是与VM密度和TAM浸润相关的关键货物。在机制上，EV递送的CAV1与DOT1L相互作用，促进DOT1L的EV装载，并驱动H3K79甲基化依赖的自噬相关5（ATG5）转录，维持VM和侵袭表型。值得注意的是，虽然抑制DOT1L可抑制VM和肿瘤进展，但它矛盾性地诱导了代偿性内皮血管生成。联合阻断DOT1L和VEGFR克服了这种代偿性反馈，实现了优异的肿瘤控制且无毒性。TAM来源的EV通过CAV1-DOT1L-ATG5轴驱动VM。我们揭示了VM与血管生成之间的代偿性联系，并证明双重靶向这两种血管模式为PDAC提供了一种有前景的治疗策略。
Abstract
Vasculogenic mimicry (VM) is a non-endothelial vascularisation programme sustaining pancreatic ductal adenocarcinoma (PDAC) perfusion and metastasis, yet its regulators and therapeutic vulnerabilities remain unclear. To elucidate the immune and epigenetic mechanisms regulating VM and identify strategies to overcome VM-driven PDAC progression. Histopathology, three-dimensional tissue clearing, spatial transcriptomics and single-cell RNA sequencing were combined to map VM distribution and its immune contexture. Tissue microarrays, co-culture assays and xenograft models were used to assess tumour-associated macrophage (TAM) contributions. Extracellular vesicle (EV) proteomics and mechanistic studies identified cargo molecules and signalling pathways. DOT1L (disruptor of telomeric silencing 1-like) inhibitor EPZ-5676 and vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib were used for therapeutic validation. VM was abundant in PDAC, increased with tumour stage and was preferentially surrounded by TAMs. M2-like TAMs promoted tube formation, invasion and tumour growth, while blockade of TAM-derived EVs abolished these effects. EV proteomics identified caveolin-1 (CAV1) as a key cargo correlating with VM density and TAM infiltration. Mechanistically, EV-delivered CAV1 interacted with DOT1L, promoted DOT1L EV loading and drove H3K79 methylation-dependent autophagy-related 5 (ATG5) transcription, sustaining VM and invasive phenotypes. Notably, while DOT1L inhibition suppressed VM and tumour progression, it paradoxically induced compensatory endothelial angiogenesis. Combined DOT1L and VEGFR blockade overcame this compensatory feedback, achieving superior tumour control without toxicity. TAM-derived EVs drive VM through a CAV1-DOT1L-ATG5 axis. We identify a compensatory link between VM and angiogenesis and demonstrate that dual targeting of these two vascular modalities offers a promising therapeutic strategy for PDAC.
如何引用
AMA
Ziyu Liu, Ying Zhang, Haonan Wu, Han Liu, Tongjia Chu, Huan Liu, et al. CAV1-DOT1L axis in TAM-derived EVs orchestrates VM and sensitises PDAC to combined VM and VEGF targeting.. Gut. 2026; doi:10.1136/gutjnl-2025-337293.
APA
Ziyu Liu, Ying Zhang, Haonan Wu, Han Liu, Tongjia Chu, Huan Liu, et al (2026). CAV1-DOT1L axis in TAM-derived EVs orchestrates VM and sensitises PDAC to combined VM and VEGF targeting.. Gut. https://doi.org/10.1136/gutjnl-2025-337293
GB/T 7714
Ziyu Liu, Ying Zhang, Haonan Wu, Han Liu, Tongjia Chu, Huan Liu, et al. CAV1-DOT1L axis in TAM-derived EVs orchestrates VM and sensitises PDAC to combined VM and VEGF targeting.[J]. Gut, 2026 doi:10.1136/gutjnl-2025-337293.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出