Mesenchymal Stem Cell-Derived Exosomes Reprogram Chemosensitivity Pathways in Cervical Cancer Spheroids

Area of Science:

• Oncology
• Cell Biology
• Biotechnology

Background:

• Cervical cancer (CC) presents a significant global health burden, often complicated by chemotherapy resistance and recurrence.
• Mesenchymal stem cell-derived exosomes (MSC-exosomes) have demonstrated a dual capacity, potentially serving as therapeutic agents while also contributing to chemoresistance.
• The precise role of MSC-exosomes in modulating chemotherapy response within cervical cancer remains incompletely understood.

Purpose of the Study:

• To investigate the impact of MSC-exosome pretreatment on the sensitivity of cervical cancer cells to chemotherapy.
• To explore the context-dependent effects of MSC-exosomes on chemoresistance and chemosensitization in three-dimensional (3D) cervical cancer spheroid models.

Main Methods:

• Generation of 3D spheroid models from HeLa and SiHa cervical cancer cell lines.
• Proteomic profiling of MSC-exosomes to identify key associated proteins.
• Assessment of MSC-exosome pretreatment effects on spheroid sensitivity to paclitaxel in combination with cisplatin or carboplatin.

Main Results:

• Proteomic analysis identified proteins like ANXA1, ANXA2, EEF2, LGALS1, and PKM2 in MSC-exosomes, linked to tumor regeneration and chemotherapy response.
• MSC-exosomes demonstrated context-dependent modulation of drug efflux, metabolic reprogramming, stress adaptation, apoptosis, DNA damage response, and integrin signaling.
• MSC-exosome pretreatment significantly enhanced chemotherapy-induced cytotoxicity in HeLa spheroids, increasing apoptosis.
• SiHa spheroids exhibited selective responses, with MSC-exosomes enhancing sensitivity to paclitaxel-carboplatin but not paclitaxel-cisplatin, particularly in the spheroid core.

Conclusions:

• MSC-exosome pretreatment exerts cell type-specific and drug-specific effects on cervical cancer spheroids.
• These findings support the potential of MSC-exosomes to modulate chemotherapy response in cervical cancer, offering avenues for novel therapeutic strategies.