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Ann Oncol. 2016 Jun;27(6):1155-60. doi: 10.1093/annonc/mdw122. Epub 2016 Mar 24.

Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study.

Author information

1
Clinical and Experimental Pharmacology Group, University of Manchester, Manchester, UK.
2
Tumour Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
3
RNA Biology Group, University of Manchester, Manchester.
4
Computational Biology Support Team, Cancer Research UK Manchester Institute, University of Manchester, Manchester.
5
The Christie NHS Foundation Trust, Manchester.
6
The Christie NHS Foundation Trust, Manchester Institute of Cancer Sciences, University of Manchester, Manchester Cancer Research UK Lung Cancer Centre of Excellence, Manchester, UK.
7
Clinical and Experimental Pharmacology Group, University of Manchester, Manchester, UK Cancer Research UK Lung Cancer Centre of Excellence, Manchester, UK caroline.dive@cruk.manchester.ac.uk.

Abstract

BACKGROUND:

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).

PATIENTS AND METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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:

circulating tumour cells; epithelial to mesenchymal transition (EMT); non-small-cell lung cancer; patient-derived circulating tumour cells explants (CDX); preclinical therapeutics

PMID:
27013395
PMCID:
PMC4880063
DOI:
10.1093/annonc/mdw122
[Indexed for MEDLINE]
Free PMC Article

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