Ren Yuqing, Ming Ruijie, Zuo Anning, Liu Shutong, Ba Yuhao, Zhang Yuyuan, Chen Yukang, Pan Teng, Luo Peng, Cheng Quan, Deng Jinhai, Yue Yi, Xu Hui, Weng Siyuan, Han Xinwei, Zhou Dongdong, Liu Zaoqu
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Oncogene. 2025 Sep 19. doi: 10.1038/s41388-025-03569-9.
The role of cancer-associated fibroblasts (CAFs) in the initiation and invasion phases of human lung adenocarcinoma (LUAD) development is not fully understood. In this study, we utilized single-cell RNA sequencing, spatial transcriptomics, and a combination of in vivo and in vitro models to decode the dynamics of tumor-stroma interactions during human LUAD progression, focusing primarily on adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). We identified a matrix CAF (mCAF) subtype characterized by high THBS2 expression, which was closely associated with poor clinical outcomes, tumor recurrence, and the invasive dynamics of LUAD. Spatial transcriptomics and multiplex immunohistochemistry analysis revealed that this CAF subpopulation was closely associated with tumor cells, with clear spatial colocalization. In vivo and in vitro experiments demonstrated that THBS2 secreted by these mCAFs directly binds to SDC4 on tumor cells, enhancing tumor epithelial-mesenchymal transition (EMT) programs. This study highlights THBS2+ mCAFs as key regulators of tumor-stroma interactions and identifies the THBS2-SDC4-EMT axis as a potential therapeutic target in LUAD.
癌症相关成纤维细胞（CAFs）在人类肺腺癌（LUAD）发生和侵袭阶段中的作用尚未完全明确。在本研究中，我们利用单细胞RNA测序、空间转录组学以及体内和体外模型相结合的方法，来解析人类LUAD进展过程中肿瘤-基质相互作用的动态变化，主要聚焦于原位腺癌（AIS）、微浸润腺癌（MIA）和浸润性腺癌（IAC）。我们鉴定出一种以高THBS2表达为特征的基质CAF（mCAF）亚型，其与不良临床预后、肿瘤复发以及LUAD的侵袭动态密切相关。空间转录组学和多重免疫组化分析显示，该CAF亚群与肿瘤细胞密切相关，存在明显的空间共定位。体内和体外实验表明，这些mCAFs分泌的THBS2直接与肿瘤细胞上的SDC4结合，增强肿瘤上皮-间质转化（EMT）程序。本研究强调THBS2+mCAFs是肿瘤-基质相互作用的关键调节因子，并确定THBS2-SDC4-EMT轴为LUAD的潜在治疗靶点。
