Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Hepatology. 2024 Jul 1;80(1):69-86. doi: 10.1097/HEP.0000000000000784. Epub 2024 Feb 20.
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.
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 in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response.
Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.
淋巴结转移是胆管癌患者的一个重要危险因素，但胆管癌在淋巴结微环境中定植的机制尚不清楚。我们旨在确定代谢重编程是否为胆管癌细胞适应和重塑淋巴结微环境提供了燃料。
在这里，我们对胆管癌患者的原发肿瘤病变和配对的淋巴结转移进行了单细胞 RNA 测序，结果显示，胆管癌转移到淋巴结后，肿瘤间异质性显著降低，并且协同的脂质代谢发生了重编程，这一结果通过泛癌症单细胞 RNA 测序分析得到了验证，突出了脂质代谢在肿瘤淋巴结定植中的重要作用。代谢组学和体内 CRISPR/Cas9 筛选鉴定出 PPARγ 是通过上调脂肪酸摄取和氧化，通过油酸-PPARγ-脂肪酸结合蛋白 4 正反馈环为胆管癌在淋巴结定植提供燃料的关键调节因子。患者来源的类器官和动物模型表明，阻断该循环会削弱胆管癌细胞在淋巴结微环境中的增殖和定植能力，并且优于全身抑制脂肪酸氧化。PPARγ 调节的胆管癌细胞脂肪酸代谢重编程还通过产生犬尿氨酸来促进淋巴结转移中的免疫抑制微环境，并且与肿瘤复发、免疫抑制性淋巴结微环境和不良的免疫检查点阻断反应相关。
我们的研究结果揭示了油酸-PPARγ-脂肪酸结合蛋白 4 循环在为胆管癌在淋巴结定植提供燃料中的作用，并表明 PPARγ 调节的脂质代谢重编程是缓解胆管癌淋巴结转移负担和减少进一步进展的有前途的治疗靶点。
