Vasculogenic mimicry in small cell lung cancer.
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.
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Stuart C
SC
Williamson
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Robert L
RL
Metcalf
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Francesca
F
Trapani
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Sumitra
S
Mohan
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Jenny
J
Antonello
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Benjamin
B
Abbott
Computational Biology Support Team, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Hui Sun
HS
Leong
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Christopher P E
CP
Chester
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Nicole
N
Simms
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Radoslaw
R
Polanski
The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
Daisuke
D
Nonaka
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Lynsey
L
Priest
The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
Alberto
A
Fusi
University of Southern California Dornsife, Los Angeles, California 90089-3301, USA.
Fredrika
F
Carlsson
University of Southern California Dornsife, Los Angeles, California 90089-3301, USA.
Anders
A
Carlsson
Stanley Manne Children's Research Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Mary J C
MJ
Hendrix
Stanley Manne Children's Research Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Richard E B
RE
Seftor
Stanley Manne Children's Research Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Elisabeth A
EA
Seftor
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Dominic G
DG
Rothwell
The Institute of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK.
Andrew
A
Hughes
University of Southern California Dornsife, Los Angeles, California 90089-3301, USA.
James
J
Hicks
RNA Biology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Crispin
C
Miller
University of Southern California Dornsife, Los Angeles, California 90089-3301, USA.
Peter
P
Kuhn
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Ged
G
Brady
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
Kathryn L
KL
Simpson
The Christie NHS Foundation Trust, Manchester M20 4BX, UK.|The Institute of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK.|Cancer Research UK, Lung Cancer Centre of Excellence, Manchester M20 4BX, UK.
Fiona H
FH
Blackhall
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.|Cancer Research UK, Lung Cancer Centre of Excellence, Manchester M20 4BX, UK.
Caroline
C
Dive
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001706:Biopsy; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D059010:Single-Cell Analysis; D055752:Small Cell Lung Carcinoma / Q000098:blood supply / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D007633:Keratins; D016159:Tumor Suppressor Protein p53; D000099152:Cadherin 5; C495901:TP53 protein, human