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

• Published in: Breast cancer research : BCR Vol. 21; no. 1; p. 98
• Main Authors: Ramani, Vishnu C, Lemaire, Clementine A, Triboulet, Melanie, Casey, Kerriann M, Heirich, Kyra, Renier, Corinne, Vilches-Moure, José G, Gupta, Rakhi, Razmara, Aryana M, Zhang, Haiyu, Sledge, George W, Sollier, Elodie, Jeffrey, Stefanie S
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 28-08-2019; BioMed Central; BMC
• Subjects: Animal models; Animals; Biology; Biomarkers, Tumor - metabolism; Blood; Brain - pathology; Breast cancer; Cancer cells; Cancer metastasis; Cancer research; Cancer therapies; Care and treatment; Cell Count; Cell Line, Tumor; Circulating tumor cells (CTCs); Cytokeratin; Epithelial-mesenchymal transition (EMT); Experiments; Female; Genetic aspects; Humans; Keratin; Keratins - metabolism; Laboratory animals; Liquid biopsy; Liver; Liver - pathology; Lung - pathology; Mammary Neoplasms, Experimental - pathology; Medical research; Metastases; Metastasis; Mice; Mice, Mutant Strains; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating - metabolism; Neoplastic Cells, Circulating - pathology; Neuroimaging; NOD scid gamma (NSG); Patient-derived orthotopic xenograft (PDOX); Patients; Phenotypes; Stem cells; Studies; Triple Negative Breast Neoplasms - pathology; Triple-negative breast cancer (TNBC); Tumor cells; Tumors; Vimentin; Vimentin - metabolism; Womens health; Xenografts; Xenotransplantation; NOD scid gamma (NSG); Liquid biopsy; Epithelial-mesenchymal transition (EMT); Patient-derived orthotopic xenograft (PDOX); Triple-negative breast cancer (TNBC); Circulating tumor cells (CTCs)
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-019-1182-4

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.
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.
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.
PDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.