Overcoming platinum-resistant ovarian cancer targeting the activated JAK-STAT pathways via extracellular vesicles

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Platinum-resistant ovarian cancer (PROC) presents a critical unmet clinical need with poorly understood molecular underpinnings.
• Extracellular vesicles (EVs) are key mediators of intercellular communication within the tumor microenvironment.
• The ascites fluid in ovarian cancer offers a unique milieu for studying PROC mechanisms.

Purpose of the Study:

• To elucidate the molecular mechanisms driving PROC, with a specific focus on the role of the ascites environment.
• To identify novel therapeutic targets for overcoming platinum resistance in ovarian cancer.

Main Methods:

• Multi-transcriptome analysis of clinical ovarian cancer samples.
• Immunohistochemistry to correlate JAK1 expression with platinum response in patients.
• In vitro and in vivo efficacy studies of JAK inhibitors in PROC models.
• Small RNA sequencing to identify microRNAs within EVs.

Main Results:

• PROC is characterized by an activated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, indicated by high JAK1 expression in cancer cells.
• Elevated JAK1 expression negatively correlates with patient response to platinum chemotherapy.
• JAK inhibitors demonstrated efficacy against PROC cell lines and xenografts, showing synergy with platinum agents.
• Activated peritoneal mesothelial cell-derived EVs, enriched in miR135a-5p, were found to enhance JAK expression and confer platinum resistance to cancer cells.

Conclusions:

• Extracellular vesicles within the ascites fluid play a crucial role in modulating platinum sensitivity in ovarian cancer.
• Targeting the JAK/STAT pathway represents a promising therapeutic strategy for overcoming PROC.
• miR135a-5p delivered via EVs contributes to platinum resistance by upregulating JAK expression.