Investigating circulating tumor cells and distant metastases in patient-derived orthotopic xenograft models of triple-negative breast cancer

• Main Authors: Vishnu C. Ramani, Clementine A. Lemaire, Melanie Triboulet, Kerriann M. Casey, Kyra Heirich, Corinne Renier, José G. Vilches-Moure, Rakhi Gupta, Aryana M. Razmara, Haiyu Zhang, George W. Sledge, Elodie Sollier, Stefanie S. Jeffrey
• Format: Article
• Language: English
• Published: BMC 2019-08-01
• Series: Breast Cancer Research
• Subjects: Circulating tumor cells (CTCs); Epithelial-mesenchymal transition (EMT); Liquid biopsy; NOD scid gamma (NSG); Patient-derived orthotopic xenograft (PDOX); Triple-negative breast cancer (TNBC)
• Online Access: http://link.springer.com/article/10.1186/s13058-019-1182-4

Abstract Background Circulating tumor cells (CTCs) represent a temporal “snapshot” of a patient’s cancer and changes that occur during disease evolution. There is an extensive literature studying CTCs in breast cancer patients, and particularly in those with metastatic disease. In parallel, there is an increasing use of patient-derived models in preclinical investigations of human cancers. Yet studies are still limited demonstrating CTC shedding and metastasis formation in patient-derived models of breast cancer. Methods We used seven patient-derived orthotopic xenograft (PDOX) models generated from triple-negative breast cancer (TNBC) patients to study CTCs and distant metastases. Tumor fragments from PDOX tissue from each of the seven models were implanted into 57 NOD scid gamma (NSG) mice, and tumor growth and volume were monitored. Human CTC capture from mouse blood was first optimized on the marker-agnostic Vortex CTC isolation platform, and whole blood was processed from 37 PDOX tumor-bearing mice. Results Staining and imaging revealed the presence of CTCs in 32/37 (86%). The total number of CTCs varied between different PDOX tumor models and between individual mice bearing the same PDOX tumors. CTCs were heterogeneous and showed cytokeratin (CK) positive, vimentin (VIM) positive, and mixed CK/VIM phenotypes. Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, less than 2%). The seven different PDOX tumor models displayed varying degrees of metastatic potential, including one TNBC PDOX tumor model that failed to generate any detectable metastases (0/8 mice) despite having CTCs present in the blood of 5/5 tested, suggesting that CTCs from this particular PDOX tumor model may typify metastatic inefficiency. Conclusion PDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.