Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment

作者：Honghua Zhang, Ke Zhu, Rui Zhang, Yabin Guo, Jin Wang, Chaoqun Liu, Xinjun Lu, Ziyu Zhou, Wenrui Wu, Fapeng Zhang, Zhixiao Song, Shusheng Lin, Caini Yang, Xiuxian Li, Yang Liu, Qibin Tang, Xianhuan Yu, Lei‐Bo Xu, Chao Liu · 发表于：Hepatology · 年份：2024 · DOI：10.1097/hep.0000000000000784 · 被引用次数：33 · 研究领域：Cancer, Lipids, and Metabolism、Ferroptosis and cancer prognosis、Cholangiocarcinoma and Gallbladder Cancer Studies

BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche i...