Extracellular Vesicle-Packaged miR-99a Reprograms Fibroblasts to Create an Inflammatory Niche That Drives Colorectal...

Area of Science:

• Oncology
• Cell Biology
• Molecular Mechanisms of Cancer

Background:

• Inflammation and epithelial-to-mesenchymal transition are key drivers of cancer progression and metastasis.
• Understanding the intercellular communication that fuels these processes is crucial for developing effective anti-cancer strategies.

Purpose of the Study:

• To investigate the role of extracellular vesicle (EV)-mediated cross-talk between colorectal cancer cells and fibroblasts in promoting metastasis.
• To elucidate the molecular mechanisms underlying this communication and identify potential therapeutic targets.

Main Methods:

• Analysis of fibroblast activation in patient tumors.
• Assessment of EV effects on fibroblast activation and colorectal cancer cell migration.
• Mechanistic studies involving microRNA (miR-99a-5p), signaling pathways (NFκB, CCR5-mTOR-p70S6K), and gene expression.
• Inhibition studies using a p70S6K inhibitor (LY2584702).
• Clinical correlation of plasma EV-miR-99a levels with metastatic status.

Main Results:

• Highly metastatic colorectal cancer cells secrete EVs that activate fibroblasts, promoting a pro-inflammatory state.
• EV-packaged miR-99a-5p targets NLRP2 in fibroblasts, activating NFκB and generating cancer-associated fibroblasts (CAFs).
• CAFs secrete CCL7, enhancing colorectal cancer cell migration and epithelial-to-mesenchymal transition via the CCR5-mTOR-p70S6K pathway.
• A positive feedback loop involving miR-99a and TGFβ1 was identified.
• Inhibition of p70S6K abolished the pro-metastatic effects.
• Plasma EV-miR-99a levels correlate with colorectal cancer metastatic status.

Conclusions:

• Extracellular vesicle-mediated communication between colorectal cancer cells and fibroblasts establishes a pro-inflammatory niche that drives metastasis.
• The identified miR-99a/TGFβ1 regulatory circuit and the p70S6K pathway are critical mediators of this process.
• EV-miR-99a serves as a potential biomarker for colorectal cancer metastasis and a target for therapeutic intervention.