Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles

Aya-Bonilla, Carlos; Gray, Elin S.; Manikandan, Jayapal; Freeman, James B.; Zaenker, Pauline; Reid, Anna L.; Khattak, Muhammad A.; Frank, Markus H.; Millward, Michael; Ziman, Mel

doi:10.3390/cancers11020157

Cited by 14 publications

(16 citation statements)

References 60 publications

(130 reference statements)

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“…The results further validated our previous observations regarding the heterogeneity of melanoma CTCs using this flow cytometry–based method . Similarly, the heterogeneity of melanoma CTCs has also been demonstrated using other isolation and detection methodologies . Previous studies have shown that that number of CTCs in patients with melanoma at baseline is prognostic of survival .…”

Section: Discussionsupporting

confidence: 87%

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

et al. 2019

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Background PD‐1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD‐L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab. Methods Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6–12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD‐L1. Results CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD‐L1+ CTCs (14/25, 64%) had significantly longer progression‐free survival (PFS) compared with patients with PD‐L1− CTCs (26.6 months vs. 5.5 months; p = .018). The 12‐month PFS rates were 76% versus 22% in the PD‐L1+ versus PD‐L1− CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD‐L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052–1.012; p = .026). Conclusion Our results reveal the potential of CTCs as a noninvasive real‐time biopsy to evaluate PD‐L1 expression in patients with melanoma. PD‐L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. Implications for Practice The present data suggest that PD‐L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.

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Section: Discussionsupporting

confidence: 87%

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

et al. 2019

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“…However, a significant proportion of late-stage melanoma patients still appear to have no CTCs detectable by CellSearch ® ( Rao et al, 2011 ; Roland et al, 2015 ; Hall et al, 2018 ). This has also been reported for other CSPG4-based methods ( Ulmer et al, 2004 ; Ruiz et al, 2015 ) as well as for CSPG4-independent isolation methods ( Khoja et al, 2014 ; Aya-Bonilla et al, 2019 ). This may simply be due to the rare nature of CTCs.…”

Section: Proteoglycans In Circulating Tumor Cell Diagnosticssupporting

confidence: 80%

“…However, to our knowledge, none of the major studies on CSPG4-positive CTCs in cutaneous melanoma have yet found any correlation between CTC levels and BRAF-mutational status or adjuvant therapy. Another recent study revealed that the transcriptomic profile of CSPG4-enriched CTC populations from six patients was dominated by up-regulation of tumor necrosis factor alpha (TNFα)/nuclear factor kappa B (NF-κB) as well as signal transducer and activator of transcription (STAT) pathways (Aya-Bonilla et al, 2019). Both signaling pathways have central roles for cell proliferation as well as cell survival (Wu and Zhou, 2010;Igelmann et al, 2019).…”

Section: Proteoglycans In Circulating Tumor Cell Diagnosticsmentioning

confidence: 99%

The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis

Ahrens

Bang-Christensen

Jørgensen³

et al. 2020

Front. Cell Dev. Biol.

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Circulating tumor cells (CTCs) are accessible by liquid biopsies via an easy blood draw. They represent not only the primary tumor site, but also potential metastatic lesions, and could thus be an attractive supplement for cancer diagnostics. However, the analysis of rare CTCs in billions of normal blood cells is still technically challenging and novel specific CTC markers are needed. The formation of metastasis is a complex process supported by numerous molecular alterations, and thus novel CTC markers might be found by focusing on this process. One example of this is specific changes in the cancer cell glycocalyx, which is a network on the cell surface composed of carbohydrate structures. Proteoglycans are important glycocalyx components and consist of a protein core and covalently attached long glycosaminoglycan chains. A few CTC assays have already utilized proteoglycans for both enrichment and analysis of CTCs. Nonetheless, the biological function of proteoglycans on clinical CTCs has not been studied in detail so far. Therefore, the present review describes proteoglycan functions during the metastatic cascade to highlight their importance to CTCs. We also outline current approaches for CTC assays based on targeting proteoglycans by their protein cores or their glycosaminoglycan chains. Lastly, we briefly discuss important technical aspects, which should be considered for studying proteoglycans.

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“…We believe that this qualitative molecular expression analysis performed on these enriched MCAM/MUC18/CD146 and/or ABC5 CMCs provides evidence that these are three distinct CMC subpopulations, sharing primitive, "stem-mesenchymal" behavior, which makes them highly aggressive and able to metastasize. Despite our smaller case series, this study is among the first (Gutiérrez garcíarodrigo et al, 2017;Aya-Bonilla et al, 2019;Zhao et al, 2019), to characterize different cancer subpopulations, contemplating a hybrid fraction, unveiling the molecular expression and suggesting distinct biological pathways activated in these cells. Molecular expression analysis especially of MCAM/MUC18/CD146, MMPs, and VE-Cadh could provide great potential and biological information to better define more aggressive CMC subpopulations and provide useful evidence to determine a suitable clinical approach, when analyzing early-AJCC-staged patients.…”

Section: Discussionmentioning

confidence: 86%

Stem–Mesenchymal Signature Cell Genes Detected in Heterogeneous Circulating Melanoma Cells Correlate With Disease Stage in Melanoma Patients

Rapanotti

Campione

Viguria

et al. 2020

Front. Mol. Biosci.

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During the process of metastasis, cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize, eventually leading to the formation of metastatic tumors. These cancer cells, defined circulating tumor cells (CTCs) spreading through the blood stream, may develop metastatic lesions or remain dormant. Some emerging clinical evidence supports that some tumor cells may possess metastatic properties already in the earlier stages of tumorigenesis. Because the initiation and progression of vertical growth in human melanoma is fundamental to the notion of tumor virulence and progression, we decided to immune-magnetic collect and molecularly characterize circulating melanoma cells (CMCs) from melanoma patients AJCC staged = pT1b (i.e., transition from radial to vertical phase). CMCs are phenotypically and molecularly heterogeneous, thus we performed a "home-made Liquid-Biopsy," by targeting the melanoma-associated-antigen, MCAM/MUC18/CD146, and/or the melanoma-initiating marker, ABCB5. We assessed a biomarker qualitative expression panel, contemplating the angiogenic-potential, melanoma-initiating and melanoma-differentiation drivers, cellcell adhesion molecules, matrix-metallo-proteinases, which was performed on three enriched subpopulations from a total of 61 blood-samples from 21 melanoma patients. At first, a significant differential expression of the specific transcripts was documented between and within the CMC fractions enriched with MCAM-, ABCB5-, and both MCAM/ABCB5-coated beads, when analyzing two distinct groups: early AJCC-(stage I-II) and advanced-staged patients (stage II-IV). Moreover, in the early-AJCC stagedgroup, we could distinguish "endothelial," CD45 − MCAM + enriched-, "stem" S-CMCs, CD45 − ABCB5 + enriched-and a third hybrid bi-phenotypic CD45 − MCAM + /ABCB5 + enriched-fractions, due to three distinct gene-expression profiles. In particular, the endothelial-CMCs were characterized by positive expression of genes involved in

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Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles

Cited by 14 publications

References 60 publications

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis

Stem–Mesenchymal Signature Cell Genes Detected in Heterogeneous Circulating Melanoma Cells Correlate With Disease Stage in Melanoma Patients

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