Abstract
Cutaneous melanoma circulating tumour cells (CTCs) are phenotypically and molecularly heterogeneous. We profiled the gene expression of CTC subpopulations immunomagnetic-captured by targeting either the melanoma-associated marker, MCSP, or the melanoma-initiating marker, ABCB5. Firstly, the expression of a subset of melanoma genes was investigated by RT-PCR in MCSP-enriched and ABCB5-enriched CTCs isolated from a total of 59 blood draws from 39 melanoma cases. Of these, 6 MCSP- and 6 ABCB5-enriched CTC fractions were further analysed using a genome-wide gene expression microarray. The transcriptional programs of both CTC subtypes included cell survival maintenance, cell proliferation, and migration pathways. ABCB5-enriched CTCs were specifically characterised by up-regulation of genes involved in epithelial to mesenchymal transition (EMT), suggesting an invasive phenotype. These findings underscore the presence of at least two distinct melanoma CTC subpopulations with distinct transcriptional programs, which may have distinct roles in disease progression and response to therapy.
Highlights
Metastatic melanoma is an aggressive tumour that is extremely difficult to treat, thought due to the heterogenous nature of the tumours [1,2]
Fifty-nine blood samples from 39 metastatic melanoma patients were subjected to circulating tumour cells (CTCs) enrichment using immunomagnetic beads conjugated to anti-MCSP or anti-ABCB5 antibodies (Table 1)
This study confirms the phenotypic and molecular heterogeneity observed in melanoma CTCs [5,9,10,11,12,33] and highlights genes and cellular pathways that may be associated with the biology of MCSP or ABCB5 CTC subtypes
Summary
Metastatic melanoma is an aggressive tumour that is extremely difficult to treat, thought due to the heterogenous nature of the tumours [1,2]. CTCs, released by all the concurrent tumours within the patient, are responsible for the haematogenous spread of the cancer. CTCs offer an accessible source to ascertain the biology of all tumours within the patient in real time and provide a biomarker to anticipate clinical outcome and monitor treatment response in a personalised manner [3,4], and perhaps a readout of the heterogeneity of melanoma tumours. CTCs have to date been shown to provide prognostic information and evidence of treatment response in real time [5,6,7,8,9]. Melanoma CTCs are known to be highly heterogeneous [5,10,11,12] and to show differential response to treatment [5,8]. More detailed phenotypic and molecular characterisation of CTCs is hindered by the lack of a ubiquitous marker for CTC detection, as reviewed by Marsavela, et al [13]
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