BACR 16: Vasculogenic mimicry in small-cell lung cancer

Francesca Trapani1,Robert Metcalf1,Cassandra Hodgkinson1,Rodoslaw Polanski1,Becky Bola1,Daisuke Nonaka2,Alberto Fusi2,Lynsey Priest1,Mary J. Hendrix3,Richard Seftor3,Elisabeth Seftor3,Christopher J. Morrow1,Jenny Antonello1,Ged Brady1,Crispin Miller4,Hui Sun Leong4,Dominic Rothwell1,Fiona Blackhall2,5,Kathryn Simpson1,Caroline Dive1,5

1CRUK MI, Manchester, Lancashire, UK,2The Christie NHS Foundation Trust, Manchester, Lancashire, UK,3Stanley Manne Children’s Research Institute, Robert H Lurie Comprehensive Cancer Center, Children’s Hospital of Chicago Research Center, Chicago, Illinois, USA,4The Institute of Cancer Sciences, University of Manchester, Manchester Lancashire, UK,5Cancer Research UK Manchester UCL Lung Cancer Centre of Excellence, Manchester and London, UK

Presenting date: Monday 2 November
Presenting time: 13.10-14.00

Background

Small cell lung cancer (SCLC) accounts for ~15% of lung cancer cases worldwide and despite initial responses to chemotherapy, most patients relapse with drug resistant disease. Targeting tumour vasculature in SCLC produced disappointing results and angiogenesis-independent tumour vascularisation pathways, including vasculogenic mimicry (VM), warrant further investigation. VM is the ability of aggressive tumour cells to form fluid conducting vascular channel-like structures. We sought to determine the role of VM in SCLC and explore the function of VE-Cadherin, a VM-associated protein in vitro and in SCLC Circulating Tumour Cells (CTCs).

Method

VM was evaluated using CD31/periodic acid-Schiff (PAS) staining in a tissue micro-array (TMA) from 41 limited stage SCLC chemo-naive patients and in tumours from 11 Circulating Tumour Cell (CTC) Derived Explant (CDX) models1. Laser Capture Microdissection (LCM) and Copy Number Analysis (CNA) were performed on CDX samples which were enriched for VM. The role of VE-Cadherin in VM was evaluated in vitro and in ISET filtered CTCs stained by IF for DAPI, CD45, cytokeratin and VE-Cadherin.

 

Results

In the TMA, VM score >10% correlated with poor OS (13.0 v 23.8 months, log rank p=0.025). VM was present in CDX models and CNA confirmed its SCLC origin. VM cells exhibited a distinct molecular signature. In vitro VE-Cadherin was essential for network formation in Matrigel and 37/38 SCLC patients contained a sub-population of VE-Cadherin expressing CTCs where the VM score ranged from 0 - 100% (median 11%, mean 21%).

Conclusion

We present the first evidence of VM in SCLC which correlates with poor OS and with findings in other cancers. VM is present in CDX models and CNA confirms that VM vessels originate from tumour, and bear a unique molecular signature. VE-Cadherin is required in SCLC for VM in vitro and VE-Cadherin co-expression was found in CTC sub-populations in SCLC.