Liquid Biopsy Method Identifies Cancer Invasiveness and Metastasis

Extensive efforts are under way to develop and validate liquid biopsy methods for cancer diagnosis and surveillance due to these techniques' low invasiveness and potential for high throughput, among other features. Among these liquid biopsy methods are nascent techniques that involve analysis of extracellular vesicles (EV), which are produced by both cancer cells and normal cells. The origins of EVs can be determined based on molecular and functional characteristics, such as the presence and activity of certain metalloproteinases (MMP), making EVs attractive candidates for liquid biopsy analytes. Zhang and colleagues developed a nanopatterned lab-on-a-chip system dubbed EV-CLUE to detect the presence and proteolytic activity of MMP14 on EVs. Using this as a readout, in vitro experiments showed that the chips were able to correctly discern cancer cells based on their invasiveness. Additional experiments using both spontaneous and xenograft-based mouse models of metastatic breast cancer demonstrated that EV-CLUE could be used to detect in vivo tumor growth and metastasis in individual mice in a minimally invasive manner. Importantly, EV-CLUE was also able to discern whether plasma specimens were derived from patients diagnosed with ductal carcinoma in situ, invasive ductal carcinoma, or locally metastatic breast cancer with an accuracy of 96.7% in a 30-patient training cohort and 92.9% in a 70-patient validation cohort. In summary, this work describes a novel EV-based liquid biopsy method with demonstrated functionality in patients. Planned future work on EV-CLUE includes adapting the technology to work with whole blood rather than plasma alone, ensuring that the chips can be manufactured at scale, validating the technique using much larger patient cohorts, and longitudinally monitoring patients with high-risk in situ breast carcinomas for development of invasive or metastatic disease.

Zhang P, Wu X, Gardashova G, Yang Y, Zhang Y, Xu L, et al. Molecular and functional extracellular vesicle analysis using nanopatterned microchips monitors tumor progression and metastasis. Sci Transl Med 2020;12:eaaz2878.

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