Targeting the ANXA8-SP1-PPA1 Axis to Modulate TCA Cycle and Matrix Deposition in Diffuse-Type Gastric Cancer

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Diffuse-type gastric cancer (DGC) is aggressive, with a dense extracellular matrix (ECM) and poorly understood metabolic reprogramming.
• Metabolic reprogramming is crucial for tumor progression and ECM deposition, but regulatory mechanisms are unclear.

Purpose of the Study:

• To identify the metabolic signature of DGC and elucidate the regulatory mechanisms linking metabolic reprogramming to ECM deposition.
• To investigate the role of Annexin A8 (ANXA8) in DGC progression and its potential as a therapeutic target.

Main Methods:

• Integrated single-cell sequencing, proteomics, metabolomics, and clinical data.
• Investigated the mechanism of ANXA8 action, including its interaction with SP1 and regulation of the tricarboxylic acid (TCA) cycle.
• Utilized organoid screening and patient-derived xenografts to test the efficacy of ANXA8 inhibition (UNC2025) and combination therapy with 5-fluorouracil (5-FU).

Main Results:

• The tricarboxylic acid (TCA) cycle is suppressed in DGC, correlating with dense ECM formation.
• ANXA8 was identified as a critical regulator that inhibits the TCA cycle, activates cancer-associated fibroblasts, and promotes ECM deposition.
• ANXA8 deletion suppressed malignancy, and targeting ANXA8 with UNC2025 restored TCA cycle activity, inhibited ECM deposition, and enhanced 5-FU efficacy.

Conclusions:

• ANXA8-mediated suppression of the TCA cycle drives ECM formation and malignant progression in DGC.
• Targeting ANXA8 represents a promising therapeutic strategy for DGC, potentially enhancing the efficacy of standard chemotherapy like 5-FU.
• UNC2025, a selective ANXA8 inhibitor, shows significant therapeutic potential, especially when delivered via a nanodelivery system.