Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study
Open Access
- 1 June 2016
- journal article
- case report
- Published by Elsevier BV in Annals Of Oncology
- Vol. 27 (6), 1155-1160
- https://doi.org/10.1093/annonc/mdw122
Abstract
Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, ‘liquid biopsies’ such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which ∼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM+) does not preclude CDX generation, highlighting epithelial to mesenchymal transition and the functional importance of mesenchymal CTCs in dissemination of this disease.Keywords
Funding Information
- British Lung Foundation (R914-6)
- Cancer Research UK (C5759/A12328)
- Manchester CRUK Experimental Cancer Medicine Centre (C1467/A15578)
- Manchester Cancer Research Centre (A12197)
- CRUK Lung Cancer Centre of Excellence (C5759/A20465)
- European Union CHEMORES (LSHG-CT-2007-037665)
This publication has 15 references indexed in Scilit:
- Patient-Derived Xenograft Models: An Emerging Platform for Translational Cancer ResearchCancer Discovery, 2014
- An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor ResistanceClinical Cancer Research, 2013
- Analysis of Circulating Tumor Cells in Patients with Non-small Cell Lung Cancer Using Epithelial Marker-Dependent and -Independent ApproachesJournal of Thoracic Oncology, 2012
- A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarkerBritish Journal of Cancer, 2011
- Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancerBritish Journal of Cancer, 2011
- Evaluation and Prognostic Significance of Circulating Tumor Cells in Patients With Non–Small-Cell Lung CancerJournal of Clinical Oncology, 2011
- Circulating Tumor Cells as a Window on Metastasis Biology in Lung CancerThe American Journal of Pathology, 2011
- Epithelial-Mesenchymal Transitions in Development and DiseaseCell, 2009
- Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate CancerClinical Cancer Research, 2008
- The IASLC Lung Cancer Staging Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant TumoursJournal of Thoracic Oncology, 2007