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Vasculogenic mimicry in small cell lung cancer.
Williamson, Stuart Metcalf, Robert Trapani, Francesca Mohan, Sumitra Antonello, Jenny Abbott, Benjamin Leong, Hui Sun Chester, Christopher P E Simms, Nicole Polanski, Radoslaw
Williamson, Stuart
Metcalf, Robert
Trapani, Francesca
Mohan, Sumitra
Antonello, Jenny
Abbott, Benjamin
Leong, Hui Sun
Chester, Christopher P E
Simms, Nicole
Polanski, Radoslaw
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Abstract
Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form 'endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.
Authors
Williamson, Stuart
Metcalf, Robert
Trapani, Francesca
Mohan, Sumitra
Antonello, Jenny
Abbott, Benjamin
Leong, Hui Sun
Chester, Christopher P E
Simms, Nicole
Polanski, Radoslaw
Nonaka, Daisuke
Priest, Lynsey
Fusi, Alberto
Carlsson, F
Carlsson, A
Hendrix, M
Seftor, R
Seftor, E
Rothwell, Dominic G
Hughes, Andrew
Hicks, J
Miller, Crispin J
Kuhn, Peter
Brady, Ged
Simpson, Kathryn L
Blackhall, Fiona H
Dive, Caroline
Metcalf, Robert
Trapani, Francesca
Mohan, Sumitra
Antonello, Jenny
Abbott, Benjamin
Leong, Hui Sun
Chester, Christopher P E
Simms, Nicole
Polanski, Radoslaw
Nonaka, Daisuke
Priest, Lynsey
Fusi, Alberto
Carlsson, F
Carlsson, A
Hendrix, M
Seftor, R
Seftor, E
Rothwell, Dominic G
Hughes, Andrew
Hicks, J
Miller, Crispin J
Kuhn, Peter
Brady, Ged
Simpson, Kathryn L
Blackhall, Fiona H
Dive, Caroline
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Date
2016-11-09
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Citation
Vasculogenic mimicry in small cell lung cancer. 2016, 7:13322 Nat Commun