Halofuginone Disrupted Collagen Deposition via mTOR-eIF2α-ATF4 Axis to Enhance Chemosensitivity in Ovarian Cancer

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling drive ovarian cancer progression, metastasis, and therapy resistance.
• Strategies targeting ECM remodeling to improve chemosensitivity in ovarian cancer are needed.

Purpose of the Study:

• To identify ECM components and therapeutic targets for enhancing ovarian cancer chemosensitivity.
• To investigate the efficacy of Halofuginone (HF) in targeting COL1A1 and its impact on the tumor microenvironment.

Main Methods:

• Developed a 22-gene matrisome signature to predict chemotherapy response and survival.
• Utilized single-cell RNA sequencing (scRNA-seq) to analyze ECM composition and macrophage infiltration.
• Screened the Encyclopedia of Traditional Chinese Medicine (ETCM) to identify COL1A1-targeting compounds, leading to Halofuginone (HF).
• Investigated the mechanism of HF action on COL1A1 production via the mTOR-eIF2α-ATF4 pathway in CAFs.

Main Results:

• A 22-gene matrisome signature predicts chemotherapy response and survival in ovarian cancer.
• COL1A1 was identified as a key ECM component contributing to chemoresistance and poor prognosis.
• Halofuginone (HF) was identified as a natural compound that inhibits COL1A1 production by targeting the mTOR-eIF2α-ATF4 axis in CAFs.
• HF treatment disrupted collagen deposition, promoted CD8+ T cell infiltration, and enhanced chemosensitivity, partly through M2-M1 macrophage polarization.

Conclusions:

• Targeting COL1A1 with Halofuginone (HF) represents a promising strategy to overcome chemoresistance in ovarian cancer.
• HF disrupts the pro-tumorigenic ECM, modulates the immune microenvironment, and enhances chemotherapy efficacy.
• Combined HF and chemotherapy treatment holds potential as an effective therapeutic approach for ovarian cancer.