PDF(Pubmed)
Abstract：
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.
摘要：
脑转移是肺癌最致命的形式。最近的研究强调了肺癌脑转移（LCBM）和原发性肺癌之间的肿瘤微环境（TME）的显着差异。这对肿瘤的进展和耐药性有很大的贡献。癌相关成纤维细胞（CAF）是具有高可塑性的促肿瘤TME的主要组成部分。然而,LCBM中CAF的谱系组成和功能仍然难以捉摸。通过重新分析肺癌患者的单细胞RNA测序（scRNA-seq）数据（GSE131907），这些患者具有不同的转移阶段，包括原发性病变和脑转移，我们发现，在缺氧情况下，在LCBM期间，CAFs经历了独特的谱系转变，这是由缺氧诱导的HIF-2α激活直接驱动的。转移的CAFs通过VEGF途径增强血管生成，触发代谢重编程，促进肿瘤细胞的生长。使用大量RNA测序数据作为验证队列。对脑转移的四个配对样品及其原发性肺癌对应物进行多重免疫组织化学（mIHC）测定以验证发现。我们的研究揭示了肺癌脑转移的新机制，其特征是HIF-2α诱导的谱系转变和CAFs的功能改变。提供了潜在的治疗靶点。
