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

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; Leibo Xu; Chao Liu

doi:10.1097/HEP.0000000000000784

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

Hepatology. 2024 Feb 20. doi: 10.1097/HEP.0000000000000784. Online ahead of print.

Authors

Honghua Zhang^{1

2

3}, Ke Zhu^{1

2

3}, Rui Zhang^{1

2}, Yabin Guo^{3

4}, Jin Wang^{3

4}, Chaoqun Liu⁵, Xinjun Lu^{1

2

3}, Ziyu Zhou^{1

2

3}, Wenrui Wu^{1

2

3}, Fapeng Zhang^{1

2

3}, Zhixiao Song^{1

2

3}, Shusheng Lin^{1

2

3}, Caini Yang^{1

2

3}, Xiuxian Li^{1

2

3}, Yang Liu^{1

2

3}, Qibin Tang^{1

2}, Xianhuan Yu^{1

2}, Leibo Xu^{1

2

3}, Chao Liu^{1

2

3}

Affiliations

¹ Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
² Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
³ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁴ Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁵ Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

PMID: 38377465
DOI: 10.1097/HEP.0000000000000784

Abstract

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 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.

Conclusions: 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.