Cancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using “liquid biopsies” to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate below 5%. Carbohydrate antigen 19-9 (CA19-9) is the most commonly used blood-based biomarker for PDAC in current clinical practice, despite having been shown repeatedly to be inaccurate and have poor diagnostic performance. This review aims to assess the reported diagnostic accuracy of all blood-based biomarkers investigated to date in PDAC, by directly comparing individual biomarkers and multi-biomarker panels, both containing CA19-9 and not (novel). A systematic review was conducted in accordance with PRISMA standards in July 2020. Individualized search strategies for three academic databases identified 5,885 studies between the years 1973 and 2020. After two rounds of screening, 250 studies were included. Data were extracted and assessed for bias. A multivariate three-level meta-analysis with subgroup moderators was run in R using AUC values as effect size. On the basis of this model, the pooled AUC value for all multi-biomarker panels (AUC = 0.898; 95% confidence interval (CI): 0.88–0.91) was significantly higher than all single biomarkers (AUC = 0.803; 95% CI: 0.78–0.83; P < 0.0001). The pooled AUC value for CA19-9 alone was significantly lower compared with the multi-biomarker panels containing CA19-9 (P < 0.0001). For the novel biomarkers, the pooled AUC for single biomarkers was also significantly lower compared with multi-biomarker panels (P < 0.0001). Novel biomarkers that have been repeatedly examined across the literature, such as TIMP-1, CEA, and CA125, are highlighted as promising. These results suggest that CA19-9 may be best used as an addition to a panel of biomarkers rather than alone, and that multi-biomarker panels generate the most robust results in blood-based PDAC diagnosis.Significance: In a systematic review and three-level multivariate meta-analysis, it is shown for the first time that blood-based multi-biomarker panels for the diagnosis of PDAC exhibit superior performance in comparison with single biomarkers. CA19-9 is demonstrated to have limited utility alone, and to perform poorly in patient control cohorts of both healthy and benign individuals. Multi-biomarker panels containing CA19-9 produce the best diagnostic performance overall.

Pancreatic cancer (PC) is regarded as one of the most lethal malignant diseases in the world, with GLOBOCAN 2020 estimates indicating that PC was responsible for almost half a million deaths worldwide in 2020. Pancreatic cystic lesions (PCLs) are fluid-filled structures found within or on the surface of the pancreas, which can either be pre-malignant or have no malignant potential. While some PCLs are found in symptomatic patients, nowadays many PCLs are found incidentally in patients undergoing cross-sectional imaging for other reasons—so called ‘incidentalomas’. Current methods of characterising PCLs are imperfect and vary hugely between institutions and countries. As such, there is a profound need for improved diagnostic algorithms. This could facilitate more accurate risk stratification of those PCLs that have malignant potential and reduce unnecessary surveillance. As PC continues to have such a poor prognosis, earlier recognition and risk stratification of PCLs may lead to better treatment protocols. This review will focus on the importance of biomarkers in the context of PCLs and PCand outline how current ‘omics’-related work could contribute to the identification of a novel integrated biomarker profile for the risk stratification of patients with PCLs and PC.

Radioresistance remains a significant challenge in treating pancreatic ductal adenocarcinoma (PDAC), contributing to the poor survival rates of this cancer. MicroRNAs (miRs) are small non-coding RNA molecules that may play an essential role in regulating radioresistance by altering the levels of oxidative stress. In this study, we investigated the role and potential mechanisms linking miR-31 to PDAC radioresistance. A pCMV-miR vector containing a miR-31 mimic was stably expressed into a miR-31-deficient PDAC cell line, BxPC-3. Additionally, a pmiRZip lentivector suppressing miR-31 was stably expressed in a miR-31 abundant PDAC cell line, Panc-1. Clonogenic assays were conducted to explore the role of miR-31 manipulation on radiosensitivity. Fluorometric ROS assays were performed to quantify ROS levels. The expression of potential miR-31 targets was measured by Western blot analysis. It was found that the manipulation of miR-31 altered the radiosensitivity in PDAC cells by regulating oxidative stress. Using online bioinformatics tools, we identified the 3′UTR of GPx8 as a predicted target of miR-31. Our study demonstrates, for the first time, that manipulating miR-31 alters GPx8 expression, regulating ROS detoxification and promoting either a radioresistant or radiosensitive phenotype. MiR-31 may represent a promising therapeutic target for altering radiosensitivity in PDAC cells.

Background: Circulating tumour cells (CTCs) are rare yet crucial biomarkers with significant prognostic potential across different cancer types. However, their role in high-grade serous ovarian cancer (HSGC) is not well defined. To capture the full spectrum of CTCs found in HGSC, we employed an EpCAM independent enrichment technique in patients with advanced HGSC and investigated the prognostic value and molecular signatures of these rare cells. Methods: CTC enumeration was performed in 43 newly diagnosed patients with HGSC using Parsortix® CTC enrichment and benchmarked against a metastatic breast cancer (MBC) cohort for which the device is FDA approved. CTCs were also isolated from the ovarian vein of patients with HGSC during primary cytoreductive surgery. CTCs were assessed as prognostic markers in patients with HGSC. FACS single cell sorting and scRNAseq was performed on CTCs isolated from the ovarian vein. Results: CTCs isolated using Parsortix® enrichment in HGSC ranged between 1-22 cells/7.5 ml blood. Concordance was seen between Parsortix® enrichment and CellSearch® enumeration in patients with MBC (R ² = 0.8786). CTC clusters were isolated from the ovarian vein ( P  = 0.0195) and were cloaked in platelets/immune cells. Detection of CTCs in patients with HGSC was predictive of a poorer progression free survival ( P  = 0.0183). Patients with CTCs were found to have increased serum levels of CD73 ( P  = 0.0311). scRNAseq of CTCs isolated from the ovarian vein identified enrichment in genes associated with immune signalling. Conclusions: Peripheral CTCs isolated from patients with HGSC were predictors of a poor prognosis. The ovarian vein was found to be a rich source of disseminating CTC clusters in HGSC. Further studies are warranted to investigate the utility of CTCs as markers of neoadjuvant chemotherapy response as well as for longitudinal monitoring. Molecular analysis of CTCs in HGSCs reveals a potential role of the immune system in CTC-mediated haematogenous metastasis.

The hallmarks of cancer and enabling characteristics are widely regarded as the key features that best define malignant disease. In a process as intricate as the development of cancer, a simple definition or stepwise series of biological events does little to encapsulate the insurmountable complexity that is this disease. Indeed, over the course of the last 25 years alone, there have been four renditions of the "Hallmarks of Cancer", each attempting to encapsulate the mechanisms involved in the development of cancer by providing a list of strict criteria that must be met in order to define the disease. With each of these four sets of principles, modern research has caused the ensuing recapitulation to be revised, and without exception, to expand. In fact, what originally began as six hallmarks of cancer, has become a list of parameters that is fourteen strong, and which aim to summarize the functional capabilities that, when acquired by human cells, provides them with the ability to form a malignant, life-threatening tumour. While at present these hallmark capabilities have largely been discussed in the context of all cancers, this review discusses each in the specific context of pancreatic cancer (PC). PC has the worst prognosis of all cancers globally, with late-stage diagnoses, aggressive tumour microenvironments, and limited treatment options contributing to the current 5-year survival rate of 13%. Here, we highlight PC-specific mechanisms underpinning each hallmark of cancer to provide a comprehensive review of the current state of knowledge around this complex disease, with the aim of aiding understanding and facilitating more meaningful research avenues.