Experimental Models of Liquid Biopsy in Hepatocellular Carcinoma Reveal Clone-Dependent Release of Circulating Tumor DNA

TY - JOUR

T1 - Experimental Models of Liquid Biopsy in Hepatocellular Carcinoma Reveal Clone-Dependent Release of Circulating Tumor DNA

AU - Labgaa, Ismail

AU - von Felden, Johann

AU - Craig, Amanda J

AU - Martins-Filho, Sebastiao N

AU - Villacorta-Martin, Carlos

AU - Demartines, Nicolas

AU - Dormond, Olivier

AU - D'Avola, Delia

AU - Villanueva, Augusto

N1 - © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.

PY - 2021/6

Y1 - 2021/6

N2 - Liquid biopsy, the molecular analysis of tumor components released into the bloodstream, has emerged as a noninvasive and resourceful means to access genomic information from cancers. Most data derived from translational studies showcase its numerous potential clinical applications. However, data from experimental models are scarce, and little is known about the underlying mechanisms and factors controlling the release of circulating tumor DNA (ctDNA) and cells (CTCs). This study aimed to model liquid biopsy in hepatocellular carcinoma xenografts and to study the dynamics of release of ctDNA and CTCs; this included models of intratumoral heterogeneity (ITH) and metastatic disease. We quantified ctDNA by quantitative polymerase chain reaction (PCR) targeting human long interspersed nuclear element group 1; targeted mutation analysis was performed with digital droplet PCR. CTCs were traced by flow cytometry. Results demonstrated the feasibility of detecting ctDNA, including clone-specific mutations, as well as CTCs in blood samples of mice. In addition, the concentration of ctDNA and presence of tumor-specific mutations reflected tumor progression, and detection of CTCs was associated with metastases. Our ITH model suggested differences in the release of DNA fragments impacted by the cell-clone origin and the treatment. Conclusion: These data present new models to study liquid biopsy and its underlying mechanisms and highlighted a clone-dependent release of ctDNA into the bloodstream.

AB - Liquid biopsy, the molecular analysis of tumor components released into the bloodstream, has emerged as a noninvasive and resourceful means to access genomic information from cancers. Most data derived from translational studies showcase its numerous potential clinical applications. However, data from experimental models are scarce, and little is known about the underlying mechanisms and factors controlling the release of circulating tumor DNA (ctDNA) and cells (CTCs). This study aimed to model liquid biopsy in hepatocellular carcinoma xenografts and to study the dynamics of release of ctDNA and CTCs; this included models of intratumoral heterogeneity (ITH) and metastatic disease. We quantified ctDNA by quantitative polymerase chain reaction (PCR) targeting human long interspersed nuclear element group 1; targeted mutation analysis was performed with digital droplet PCR. CTCs were traced by flow cytometry. Results demonstrated the feasibility of detecting ctDNA, including clone-specific mutations, as well as CTCs in blood samples of mice. In addition, the concentration of ctDNA and presence of tumor-specific mutations reflected tumor progression, and detection of CTCs was associated with metastases. Our ITH model suggested differences in the release of DNA fragments impacted by the cell-clone origin and the treatment. Conclusion: These data present new models to study liquid biopsy and its underlying mechanisms and highlighted a clone-dependent release of ctDNA into the bloodstream.

U2 - 10.1002/hep4.1692

DO - 10.1002/hep4.1692

M3 - SCORING: Journal article

C2 - 34141992

VL - 5

SP - 1095

EP - 1105

JO - HEPATOL COMMUN

JF - HEPATOL COMMUN

SN - 2471-254X

IS - 6

ER -