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Title: Human-specific RNA analysis shows uncoupled epithelial-mesenchymal plasticity in circulating and disseminated tumour cells from human breast cancer xenografts.
Austin Authors: Tachtsidis, Anthony;Le, Anh Viet-Phuong;Blick, Tony;Gunasinghe, Devika;De Sousa, Emma;Waltham, Mark;Dobrovic, Alexander ;Thompson, Erik W
Affiliation: The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Prescot Road, Liverpool, UK
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
Translational Research Institute, Brisbane, QLD, Australia
University of Melbourne Department of Surgery, St. Vincent's Hospital, Melbourne, VIC, Australia
St. Vincent's Institute, Melbourne, VIC, Australia
Issue Date: 2019 2019-06-12
Publication information: Clinical & experimental metastasis 2019; 36(4): 393-409
Abstract: Blood samples, bone marrow, tumours and metastases where possible were collected from SCID mice bearing orthotopic xenografts of the triple-negative MDA-MB-468 cell line or a transplantable ER-positive patient derived xenograft (ED-03), and assessed using human-specific, tandem-nested RT-qPCR for markers relating to detection of circulating (CTCs) and disseminated tumour cells (DTCs), breast cancer clinicopathology, the 'cancer stem cell' phenotype, metabolism, hypoxia and epithelial-mesenchymal plasticity (EMP). Increased levels of SNAI1, ILK, NOTCH1, CK20, and PGR, and a decrease/loss of EPCAM in CTCs/DTCs were observed relative to the primary xenograft across both models. Decreased CD24 and EGFR was restricted to the MDA-MB-468 model, while increased TFF1 was seen in the ED-03 model. The major metabolic regulator PPARGC1A, and several hypoxia-related markers (HIF1A, APLN and BNIP3) were significantly elevated in both models. Increased expression of mesenchymal markers including SNAI1 was seen across both models, however CDH1 did not decrease concordantly, and several other epithelial markers were increased, suggesting an uncoupling of EMP to produce an EMP hybrid or partial-EMT. Single cell analysis of ED-03 CTCs, although limited, indicated uncoupling of the EMP axis in single hybrid cells, rather than distinct pools of epithelial or mesenchymal-enriched cells, however dynamic heterogeneity between CTCs/DTCs cannot be ruled out. Reduced CD24 expression was observed in the MDA-MB-468 CTCs, consistent with the 'breast cancer stem cell' phenotype, and metastatic deposits in this model mostly resembled the primary xenografts, consistent with the mesenchymal-epithelial transition paradigm.
DOI: 10.1007/s10585-019-09977-y
ORCID: 0000-0002-9723-4924
PubMed URL: 31190270
Type: Journal Article
Subjects: Breast cancer (BC)
Circulating tumour cell (CTC)
Disseminated tumour cell (DTC)
Epithelial-mesenchymal plasticity (EMP)
Epithelial-mesenchymal transition (EMT)
Mesenchymal-epithelial transition (MET)
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