S100A14 in Tumor-Derived EVs Targets PIAS3 to Reprogram Astrocytes and Induce Immunosuppressive Microenvironment...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Brain metastasis (BrM) is a major cause of mortality in cancer patients, with unclear pathogenesis and limited therapeutic options.
• Tumor-derived exosomes (EVs) play a significant role in cancer progression, but their specific contributions to BrM are not fully understood.

Purpose of the Study:

• To identify key molecular mediators of exosome-driven brain metastasis.
• To elucidate the underlying molecular mechanisms of S100A14 in promoting BrM.
• To evaluate the therapeutic potential of germacrone against S100A14-mediated BrM.

Main Methods:

• Proteomic analysis (DIA) to quantify protein expression in BrM-EVs.
• In vivo mouse models (intracardiac injection) to assess the role of S100A14-overexpressing EVs in BrM.
• Mechanistic studies involving astrocyte reprogramming, STAT3 signaling, and chemokine secretion.
• In vitro and in vivo evaluation of germacrone's efficacy and toxicity.

Main Results:

• S100A14 was consistently overexpressed in BrM-EVs from cell lines and clinical samples.
• S100A14-overexpressing EVs significantly promoted BrM in preclinical models of lung and breast cancer.
• S100A14 reprograms astrocytes via PIAS3/STAT3 signaling, leading to recruitment of immunosuppressive cells (MDSCs).
• Germacrone effectively inhibited BrM progression by directly targeting S100A14, disrupting its interaction with PIAS3, and reducing MDSC recruitment, with no significant toxicity.

Conclusions:

• S100A14 is a critical mediator of tumor exosome-driven brain metastasis.
• Germacrone demonstrates significant therapeutic potential for preventing BrM by targeting S100A14.