Microenvironmental pH is a key factor for exosome traffic in tumor cells

Area of Science:

• Cell Biology
• Oncology
• Biochemistry

Background:

• Exosomes are key mediators of intercellular communication, carrying diverse molecules.
• Tumor microenvironments often exhibit acidic pH, a characteristic of malignancy.
• Mechanisms of tumor exosome trafficking, release, and transmission remain incompletely understood.

Purpose of the Study:

• To investigate the influence of pH on exosome release, uptake, and fusion dynamics in melanoma.
• To elucidate the biophysical properties of exosomes under acidic conditions.
• To explore the role of exosome delivery in tumor malignancy and identify potential therapeutic targets.

Main Methods:

• Exosomes were purified from metastatic melanoma cells and labeled with a lipid fluorescent probe (R18).
• Spectrofluorometry and confocal microscopy were used to analyze exosome trafficking under varying pH conditions.
• Membrane biophysical analyses assessed exosome fluidity and lipid composition.
• Proton pump inhibitors were used to evaluate their effect on exosome uptake.

Main Results:

• Low pH significantly increased exosome release and uptake by melanoma cells compared to buffered conditions.
• Exosome uptake occurred via fusion, with increased efficiency at low pH.
• Exosomes released at low pH exhibited higher rigidity and sphingomyelin/ganglioside GM3 content, enhancing fusion.
• Metastatic melanoma cells showed higher exosome fusion efficiency than primary or normal cells.
• Caveolin-1, a protein linked to melanoma progression, was highly delivered via exosomes in acidic conditions.

Conclusions:

• Tumor-derived exosomes are efficiently trafficked and internalized through fusion, particularly under acidic conditions.
• The biophysical properties of exosomes are modulated by pH, influencing their fusion efficiency.
• Exosomes act as a delivery system for molecules promoting tumor malignancy, highlighting their role in paracrine diffusion.
• Targeting tumor pH and exosome function presents a promising strategy for novel anti-cancer therapies.