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

Area of Science:

• Oncology
• Metabolic Biology
• Cancer Metastasis

Background:

• Lymph node metastasis is a critical factor in cholangiocarcinoma patient prognosis.
• The mechanisms of cholangiocarcinoma adaptation within the lymph node microenvironment are not well understood.

Purpose of the Study:

• To investigate if metabolic reprogramming drives cholangiocarcinoma cell adaptation and remodeling in lymph nodes.
• To identify key metabolic pathways and regulators involved in lymph node metastasis.

Main Methods:

• Single-cell RNA sequencing of primary tumors and lymph node metastases.
• Pan-cancer single-cell RNA sequencing analysis.
• Metabolomics and in vivo CRISPR/Cas9 screening.
• Patient-derived organoids and animal models.

Main Results:

• Cholangiocarcinoma exhibits reduced intertumor heterogeneity and distinct lipid metabolic reprogramming in lymph node metastases.
• The oleic acid-PPARγ-fatty acid-binding protein 4 (FABP4) feedback loop was identified as crucial for lymph node colonization by upregulating fatty acid uptake and oxidation.
• Inhibition of this loop significantly impaired cholangiocarcinoma proliferation and colonization.
• PPARγ-regulated lipid metabolism contributes to an immune-suppressive niche and is linked to tumor relapse and poor response to immunotherapy.

Conclusions:

• The oleic acid-PPARγ-FABP4 loop is essential for cholangiocarcinoma lymph node colonization.
• Targeting PPARγ-regulated lipid metabolic reprogramming presents a promising therapeutic strategy for cholangiocarcinoma lymph node metastasis.
• This approach may help reduce metastasis burden and disease progression.