脑转移是最具破坏性的肺癌形式。最近的研究强调了肺癌脑转移（LCBM）和原发性肺癌之间肿瘤微环境（TME）的显着差异，这对肿瘤进展和耐药性有显着影响。癌症相关成纤维细胞（CAF）是促肿瘤TME的主要成分，具有高度可塑性。然而，LCBM 中 CAF 的谱系组成和功能仍然难以捉摸。通过重新分析来自不同转移阶段（包括原发灶和脑转移）的肺癌患者的单细胞RNA测序（scRNA-seq）数据（GSE131907），我们发现CAF在缺氧情况下的LCBM过程中经历了独特的谱系转变，这直接导致了CAF的谱系转变。由缺氧诱导的 HIF-2α 激活驱动。转移的 CAF 通过 VEGF 途径增强血管生成，触发代谢重编程，并促进肿瘤细胞的生长。大量 RNA 测序数据被用作验证队列。对四对脑转移瘤及其原发性肺癌样本进行多重免疫组织化学 (mIHC) 测定，以验证研究结果。我们的研究揭示了一种肺癌脑转移的新机制，其特点是 HIF-2α 诱导的谱系转变和 CAF 功能改变，这提供了潜在的治疗靶点。© 2024 作者。由泰勒授权出版

Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.