Circulating Extracellular Vesicles Reflect Dynamic Shifts in Liver Transcriptome Following Tumour Resection

Background/Objectives: Poor outcomes in liver cancer are often driven by late-stage diagnoses and high recurrence rates following surgical resection, highlighting a critical clinical need for non-invasive surveillance tools. This proof-of-concept study investigates the utility of circulating extracellular vesicles (EVs) to track dynamic molecular shifts and monitor patient response following tumour resection. Methods: Small ribonucleic acid (RNA) sequencing was conducted on matched tumour tissue, tissue-derived EVs, and plasma EVs collected at the time of surgery from patients with liver cancer. To capture longitudinal transcriptomic changes, plasma EVs were also collected at a post-operative follow-up appointment. Results: At the time of surgery, the transcriptomic profile of circulating plasma EVs strongly correlated with both the matched tumour tissue and tissue-derived EVs, exhibiting substantial transcript overlap. However, at post-operative follow-up, the circulating EV cargo significantly diverged from the primary tumour profile. This loss of similarity was characterised by a distinct shift in RNA cargo, including 173 uniquely detected transcripts absent at baseline. Conclusions: Circulating EVs accurately reflect the local hepatic transcriptome at the time of surgery, but their profile dynamically and fundamentally diverges once the tumour is removed. This post-surgical divergence provides an initial proof-of-concept that utilising patients as their own internal control to longitudinally profile EV cargo may track the clearance of tumour signals and monitor post-surgical systemic changes, highlighting their potential utility for future longitudinal studies aimed at tracking cancer progression and recurrence.