PDAC peripheral and portal vein sampling
Research type
Research Study
Full title
Collection of Peripheral and Portal Vein blood from Patients with Pancreatic Adenocarcinoma for Translational Research
IRAS ID
243841
Contact name
Juan Valle
Contact email
Sponsor organisation
The Christie NHS Foundation Trust
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Research Summary
This is a research study in which bio-specimens (whole blood, plasma and serum from peripheral circulation and portal vein) will be collected from patients with pancreatic adenocarcinoma for translational research. These samples will be used for (but not limited to) identification and characterisation of blood-borne biomarkers at the genomic and protein expression level. Examples of such biomarkers are circulating tumour cells (CTCs), CTC clusters and circulating DNA (which can be tumour derived, or from unaffected/normal cells). CTC-enriched blood samples may also be used to generate CTC-derived tumour explant (CDX) models in immunocompromised mice in order to produce suitable disease models in which to test novel therapies and identify new molecular targets. In addition, permission will be sought from study participants for the research team to access clinical information from medical notes to aid in determining the clinical relevance of biomarkers identified during the course of this study. Validated biomarkers are anticipated to be used in designing future biomarker-directed clinical trials in these disease groups.Summary of Results
Clinical management of pancreatic ductal adenocarcinoma (PDAC) is challenging; most patients present with metastatic disease and offered limited treatment options. Yet, several aspects of the metastatic dissemination process are poorly defined in PDAC. Cells that detach from the primary tumour and, through haematogenous spread, reach distant organs are central to the development of metastatic deposits. These cells can be detected in the circulation of patients with PDAC either as single Circulating Tumour Cells (CTCs) or as parts of CTC clusters. However, they remain poorly characterised. Specifically, their heterogeneity and functional role need to be further elucidated and their potential to serve as biomarkers in clinical practise needs to be assessed.We have have set up the ‘PDAC peripheral and portal vein sampling’ study to enable acquisition and analysis of blood from the main tumour draining vessel (the portal vein) in patients with locally advanced or metastatic PDAC. Following CTC enrichment, we employed a multimodal approach to describe the phenotypic and genetic CTC landscape. More specifically, immune fluorescent staining and image analysis methods where optimised for enumeration and morphologic characterisation of CTCs and CTC clusters. Moreover, single cell whole genome and targeted gene next generation sequencing was utilised for CTC genomic analysis. Finally, imaging mass cytometry protocols were developed to delineate the cellular composition of CTC clusters.
This revealed significant heterogeneity in the number of portal vein CTCs and CTC clusters across patients with advanced stage tumours, with larger CTC numbers observed in metastatic compared to patients with locally advanced disease. Single CTCs of various phenotypes and morphologies as well as epithelial and mixed CTC clusters were observed. Imaging mass cytometry provided preliminary evidence that these mixed clusters likely consist of epithelial cells co-circulating with immune cells. Interestingly, genomic analysis revealed that a significant proportion of isolated circulating cells and clusters, considered of malignant origin based on their immune phenotype, harbour diploid genomes and no KRAS mutations.
Confirmation of results described in this study by analysis of more CTCs and CTC clusters in larger patient cohorts would be required to determine the potential these cells hold in gaining insight into the biology of PDAC metastasis. This project provides initial evidence as well as the tools for further studies with the ultimate aim to incorporate CTCs in clinical decision making and improve the lives of patients with PDAC.
REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
18/NW/0569
Date of REC Opinion
28 Aug 2018
REC opinion
Favourable Opinion