Human-specific RNA analysis shows uncoupled epithelial-mesenchymal plasticity in circulating and disseminated tumour cells from human breast cancer xenografts

AbstractBlood 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 ofSNAI1,ILK,NOTCH1,CK20, andPGR, and a decrease/loss ofEPCAM in CTCs/DTCs were observed relative to the primary xenograft across both models. DecreasedCD24 andEGFR was restricted to the MDA-MB-468 model, while increasedTFF1 was seen in the ED-03 model. The major metabolic regulatorPPARGC1A, and several hypoxia-related markers (HIF1A,APLN andBNIP3) were significantly elevated in both models. Increased expression of mesenchymal markers includingSNAI1 was seen across both models, howeverCDH1 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. ReducedCD24 expression was observed in the MD...
Source: Clinical and Experimental Metastasis - Category: Cancer & Oncology Source Type: research