肺癌是死亡率最⾼的恶性肿瘤，复发转移是导致患者死亡的主要原因。沿气腔播散（STAS）被证实为肺癌新的侵袭转移方式，是肺腺癌独立预后因素，但目前其形成机制尚未阐明。我们研究发现肺腺癌STAS与上皮间质转化（EMT）密切相关并伴随M2型巨噬细胞聚集，后者可显著促进EMT。基于前期肺癌miRNAs研究，我们从TCGA数据库筛选出与肺腺癌STAS显著相关的miR-323b-3p，并证实其在肺腺癌外泌体中高度富集。靶基因预测及信号通路分析表明miR-323b-3p可通过下调SOCS激活JAK/STAT通路诱导巨噬细胞M2极化。据此我们提出外泌体miR-323b-3p通过诱导巨噬细胞M2极化促进EMT导致STAS形成的科学假说。本项目拟从血浆、细胞及动物水平观察肺腺癌外泌体miR-323b-3p对巨噬细胞M2极化、肿瘤细胞EMT及STAS形成的调控，为肺腺癌侵袭转移分子预测及靶向治疗提供新的理论依据。

Lung cancer is the leading cause of cancer-related death worldwide. Recurrent and metastatic disease are the primary causes of death for lung cancer patients. Tumor spread through air space (STAS), as a newly identified invasion pattern, was proved to be an independent prognostic factor for lung adenocarcinoma (LUAD). However, the underlying mechanism of STAS is still unclear. We discovered that STAS was highly correlated with epithelial-mesenchymal transition (EMT), and concomitant with accumulation of M2 macrophages, which could significantly promote EMT. On the basis of our previous research work of lung cancer related miRNAs, we proved that miR-323b-3p was significantly associated with STAS in LUAD using TCGA database. Preliminary experiments also showed that miR-323b-3p was highly enriched in LUAD-drived exosomes. Furthermore, target genes prediction and signal pathway analysis suggested that miR-323b-3p could drive M2 macrophages polarization via down-regulating SOCS and activating JAK/STAT pathway. Hereby, we propose that exosomal miR-323b-3p drives M2 macrophage polarization to promote EMT and leads to STAS in LUAD. In this proposal, we are aiming to investigate the regulation of LUAD-drived exosomal miR-323b-3p on M2 macrophage polarization, EMT and STAS in vivo and in vitro (LUAD patient plasma, cultured cells and nude mice). These studies will provide new theoretical basis for molecular prediction and target therapy of LUAD invasion and metastasis.