The lab: Callewaert group

Lab's research themes:

We are a large medical biotechnology group with two main broad areas of activity: development of bioanalytical technology with potential diagnostic utility, and bio-engineering of cells of biopharmaceutical importance.

Key enabling areas of technical expertise in the lab are glyco-biotechnology, genetic engineering, bio-organic chemistry, biopharmaceutical protein production in the eukaryotic secretory system, immunological analysis and enzyme-based analytics. At the interfaces of these expertises, we define new basic biotechnology research projects that are initiated to answer to unmet needs in biomedical research, diagnostics and therapeutics, in line with the strategy of the Center.

The lab enters into a new research line only if there is a clear opportunity to break through important barriers to progress, through our in-house development of new methods and tools that build on unique capabilities of the group and its environment. In general, students and postdocs come to our lab because they want to innovate and invent to enable breakthrough research and new medically useful tools. Students and postdocs are trained in working in a biotech environment, and not surprisingly, most go on to develop research careers in biotech R&D in companies, where their profile is in high demand.

Merits of the lab:

We have a long standing collaboration with the hepatology department at the University Hospital in Ghent for the develoment of glycomics-based biomarkers (prof. dr. Hans Van Vlierberghe and dr. Xavier Verhelst). More recently, we have expanded our biomarker research to a multi-omics and multi-center setting. We are working together with two additional academic hospitals, the University Hospital in Antwerp (UZA, prof. dr. Sven Francque) and the University Hospital in Leuven (prof. dr. David Cassiman) to explore and validate biomarkers in NASH/NAFLD and in early HCC detection and risk stratification. Together with these three hospitals we have been collecting liquid biopsies for biomarker discovery using proteomics, transcriptomics, methylomics, glycomics and metabolomics.

Further, we have many running and starting collaborations in the field of oncology diagnostics development, mainly with the goal of classifying tumors for treatment guidance or for prognosis. This is based on our cfRRBS technology (De Koker A. et al. A versatile method for circulating cell-free DNA methylome profiling by reduced representation bisulfite sequencing. bioRxiv 663195; doi: Below, we list the most important collaborations in oncology:

1. Lymphoma classification for treatment guidance, with AZ Delta (Dries Deeren)
2. Pediatric tumor classification for treatment guidance, with UZ Ghent (Bram De Wilde & Katleen De Preter)
3. Cancers of Unknown Primary classification for treatment guidance with UZ Ghent (Jo Van Dorpe & Katleen De Preter)
4. Prostate cancer classification for prognosis, with UZ Ghent (Piet Ost & Katleen De Preter)
5. Oesophagus tumor classification for treatment guidance and pancreas tumor biomarker selection for operability, with UZ Ghent (Katleen De Preter)
6. Lymphoma, Lung and brain cancer classification for treatment guidance, with UZ Ghent (Jo Van Dorpe)

Why do we want medical doctors?

We are a large research group with a good balance of technical staff, PhD students, postdocs and staff scientists. People are selected based on their scientific merits, irrespective of gender, origin, nationality, or background.

Diversity in skills and expertise (analytics, bio-organic chemistry, data science, animal models, protein engineering and biochemistry, cell biology) is essential in the functioning of our lab, with many different profiles contributing to the success of our research lines. It's no overstatement to say that there are few life science labs in the world where such a diverse group of scientists are brought together.

The result is a collaborative open atmosphere where people support each other’s experiments and new angles on a problem are never far away. Since most our research is somehow medically oriented, collaborations with clinicians are self-evident. We often have hosted visiting MD(-PhD's), performing a part of their research in our lab and the logical next step is to host an MD as a permanent lab member.

Country: Belgium
Supervisor: Nico Callewaert

The position

What’s the main purpose of our research?

We propose a project in the field of hepatocellular carcinoma diagnostics that will build on and bring together several research lines in our lab: N- and O-glycomics and methylomics (see below for more methodological details). These methods have been designed with clinical applicability in mind (both with respect to implementation and cost) and have now reached a point of maturity that they are being used for biomarker discovery in several clinical settings.

The current research project would pursue the discovery of biomarkers for early HCC diagnosis and HCC risk stratification in liver cirrhosis patients using these omics technologies. A large number of high quality samples from several Belgian university hospitals are already available. Further targets are biomarkers for treatment follow-up and prediction of drug response. For the latter, we will expand our collaboration with the hepatology department at UZ Ghent (prof. dr. Hans Van Vlierberghe and dr. Xavier Verhelst), who are experts in the field of hepatocellular carcinoma.

How we will do it?

Over the past 3 years, liquid biopsies have being prospectively collected at the hepatology departments in three clinical centers (UZ Gent, UZ Antwerp and UZ Leuven). These samples enable a full multi-omics characterization of cirrhosis and early HCC patients and should give this project a kick start. In particular, these samples will be characterized with epigenomics (methylomics) and glycomics workflows developed in our lab. These give access to a layer of molecular information that is not directly genetically coded and thus carries physiologically relevant information.

First, we have a two decade-long experience using glycomics in chronic liver disease. Most of the plasma proteome and thus also the plasma glycome is produced by the hepatocytes. The glycome changes with the physiological state of the cells and consequently carries disease information. Our research has resulted in a cirrhosis biomarker and a HCC risk stratification marker based on the N-glycans in the plasma proteome (Callewaert N. et al. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med 10, 429–434 (2004), Verhelst X. et al. A Glycomics-Based Test Predicts the Development of Hepatocellular Carcinoma in Cirrhosis. Clin Cancer Res 23, 2750–2758 (2017)). Currently we are developing a method that allows to characterize the O-glycome on tissue and secreted proteins. Via this method, we should be able to collect valuable information of cell-surface glycoproteins markers that are tumor-specific.

On the methylomics side, we have developed cfRRBS, cell-free reduced representation bisulphite sequencing, that allows to profile methylation of cell-free DNA (De Koker A. et al. A versatile method for circulating cell-free DNA methylome profiling by reduced representation bisulfite sequencing. bioRxiv 663195; doi: CpG methylation has a profound regulatory effect on protein expression and often changes during oncogenesis. The goal is to find early HCC detection biomarkers and, based on the specific tumor epigenomics profile, enable the prediction of drug response.
Much of the clinical work in the past has been done in collaboration with the hepatology department at UZ Ghent and we intend to continue this work together. The combination of our experience in method development with the clinical expertise in the hepatology field of Dr. Van Vlierberghe and Dr. Verhelst ensure an environment in which this project can be brought to fruition successfully.

Why is this important?

Chronic liver disease is a major cause of morbidity and mortality worldwide, with increasing prevalence. In terms of total years of life lost, it is now the 13th most burdensome disease overall and the 5th leading cause of death in the young adult age group of 25-50 years. HCC costs 800,000 lives per year. The main etiologies are chronic hepatitis B and C virus infection (HBV, HCV), alcohol abuse and, rapidly increasingly, nonalcoholic fatty liver disease (NAFLD) that is associated with insulin resistance and obesity. NAFLD is dramatically increasing in the last decades, in parallel with the obesity epidemic that is hitting hard in countries with a western diet.

In this setting, there are several unmet clinical needs with respect to diagnosis and follow up. In particular demand are biomarkers for early detection of HCC, while it is still in a stage amenable to curative treatment (as opposed to life-prolonging and supportive treatment). During treatment, there is a need for accurate disease monitoring biomarkers; how is the disease progressing? Does the treatment have a beneficial effect? Taking it one step further towards personalized medicine, (methylomics ) profiling of a patient’s HCC should allow to predict future drug responses and we can even envisage designing a personalized immunotherapy based on glycoprotein targets that we identify.

Who is a good fit for the project?

Experience in clinical or translational research in the field of hepatology or pathology in general. Experience or keen interest in exploring novel wet lab technologies, and (omics) data analyses.

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