Extracellular Vesicles as Liquid Biopsy Biomarkers across the Cancer Journey: From Early Detection to Recurrence.

BACKGROUND: Cancer is a dynamic process and thus requires highly informative and reliable biomarkers to help guide patient care. Liquid-based biopsies have emerged as a clinical tool for tracking cancer dynamics. Extracellular vesicles (EVs), lipid bilayer delimited particles secreted by cells, are a new class of liquid-based biomarkers. EVs are rich in selectively sorted biomolecule cargos, which provide a spatiotemporal fingerprint of the cell of origin, including cancer cells. CONTENT: This review summarizes the performance characteristics of EV-based biomarkers at different stages of cancer progression, from early malignancy to recurrence, while emphasizing their potential as diagnostic, prognostic, and screening biomarkers. We discuss the characteristics of effective biomarkers, consider challenges associated with the EV biomarker field, and report guidelines based on the biomarker discovery pipeline. SUMMARY: Basic science and clinical trial studies have shown the potential of EVs as precision-based biomarkers for tracking cancer status, with promising applications for diagnosing disease, predicting response to therapy, and tracking disease burden. The multi-analyte cargos of EVs enhance the performance characteristics of biomarkers. Recent technological advances in ultrasensitive detection of EVs have shown promise with high specificity and sensitivity to differentiate early-cancer cases vs healthy individuals, potentially outperforming current gold-standard imaging-based cancer diagnosis. Ultimately, clinical translation will be dictated by how these new EV biomarker-based platforms perform in larger sample cohorts. Applying ultrasensitive, scalable, and reproducible EV detection platforms with better design considerations based upon the biomarker discovery pipeline should guide the field towards clinically useful liquid biopsy biomarkers.

Proteomic Profiling of Fallopian Tube-Derived Extracellular Vesicles Using a Microfluidic Tissue-on-Chip System.

The human fallopian tube epithelium (hFTE) is the site of fertilization, early embryo development, and the origin of most high-grade serous ovarian cancers (HGSOCs). Little is known about the content and functions of hFTE-derived small extracellular vesicles (sEVs) due to the limitations of biomaterials and proper culture methods. We have established a microfluidic platform to culture hFTE for EV collection with adequate yield for mass spectrometry-based proteomic profiling, and reported 295 common hFTE sEV proteins for the first time. These proteins are associated with exocytosis, neutrophil degranulation, and wound healing, and some are crucial for fertilization processes. In addition, by correlating sEV protein profiles with hFTE tissue transcripts characterized using GeoMx® Cancer Transcriptome Atlas, spatial transcriptomics analysis revealed cell-type-specific transcripts of hFTE that encode sEVs proteins, among which, FLNA, TUBB, JUP, and FLNC were differentially expressed in secretory cells, the precursor cells for HGSOC. Our study provides insights into the establishment of the baseline proteomic profile of sEVs derived from hFTE tissue, and its correlation with hFTE lineage-specific transcripts, which can be used to evaluate whether the fallopian tube shifts its sEV cargo during ovarian cancer carcinogenesis and the role of sEV proteins in fallopian tube reproductive functions.