CRC is the second most common cancer in Europe1, and is one of the most curable cancers when detected in its early stages, which, however, often remain undiagnosed due to their aspecific symptoms. Population-based screenings for early detection have proven very effective2 but current CRC screening methods either lack sensitivity and/or specificity, or cause discomfort and pain due to their invasive character 3,4,5. Moreover, the heterogeneous nature of CRC leads to highly variable disease progression and outcome as well as treatment response, resulting in an urgent need for personalized treatment and biomarkers. Although several CRC plasma biomarkers at DNA, protein as well as carbohydrate level have been proposed, they have not yet reached clinical application, with the exception of CEA levels in the circulation which are of limited value6.
Carbohydrates attached to proteins or lipids (glycans) are promising candidates as diagnostic and prognostic CRC biomarkers, since various studies have shown CRC-associated changes in glycosylation profiles, which were able to distinguish CRC from control tissue and plasma. Alterations of glycan structures can affect their interactions with glycan-binding proteins, having, as a result, profound consequences on cellular processes, such as tumour progression, metastasis and immuno response to tumours7. Adding information on glycan changes to screenings of protein levels is therefore a promising biomarker, as demonstrated by two tumour-derived glycan antigens currently being used in clinics for hepatocellular8 and pancreatic cancer9 diagnostics.
The main GlyCoCan scientific objective is therefore enhancing the understanding on the structure-function relationship of glycosylation in CRC to find improved diagnostic and prognostic biomarkers and pave the way for novel therapeutic targets.
Our three main research objectives are:
- Characterization of CRC-glycosylation with link to genetic alterations and disease stage;
- In vitro and in vivo evaluation of the role of glycosylation in immune modulation in CRC;
- Development and validation of novel tools for enhanced clinical diagnostics and therapeutic strategies, i.e. via plasma-derived glycan biomarkers and improved antibodies.
These objectives will be the main target of 3 interdependent work packages, for which different expertises will be combined. Among others:
- Effective purification of glycans and glycoproteins from CRC cell lines and patient tissues combined with sensitive analytics
- Functional high-throughput microarray transcriptome analysis,
- In vivo imaging and in vitro study of migration and invasiveness/adhesiveness of different CRC cells with modifications in glyco-genes.
- In vitro targeting of human immune cells with genetically modified CRC cell lines
- In vivo validation of the results in different mouse models including e.g. in vivo bioluminescence imaging
- Developing antibodies with improved CRC-specificity
- Robust analytical workflow for the specific and sensitive determination of N-glycosylation in CEA and TIMP-1 from plasma and CRC cell lines
- Evaluating the prognostic and diagnostic value of glycosylation of total plasma proteins as well as of immunoglobulin (Ig) G and A, CEA, TIMP-1, and haptoglobin isolated from human plasma from large CRC patient cohorts
- High-throughput MS-based assay using synthetic glycopeptides
2 K. Y. C. Fung et al. World J Gastroenterol. 20, 888 (Jan 28, 2014).
3 T. R. de Wijkerslooth et al. Gut 61, 1552 (Nov, 2012).
4 B. Levin et al. Gastroenterology 134, 1570 (May, 2008).
5 R. Siegel et al. CA: a cancer journal for clinicians 64, 104 (Mar-Apr, 2014).
6 C. Compton et al. Cancer 88, 1739 (Apr 1, 2000).
7 Adamczyk et al. Biochem Biophys Acta 1820, 1347 (2012)
8 S. Moriya et al. Anticancer research 33, 997 (Mar, 2013).
9 M. J. Duffy et al. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 21, 441 (Mar, 2010).
The GlyCoCan consortium offers trainings in the fields of (structural) glycobiology, carbohydrate (bio) chemistry, (cancer) glycoproteomics and glycomics, glyco-immunology, oncology, haematology and pathology, quality management as well as industrial RD&I experiences.
Training is provided thourgh 13 individual inter-disciplinary Early Stage Research projects, which target different aspects of the GlyCoCan scientific program and which combined guarantee the coverage of all the research objectives.
The main training consists of a doctoral research project, complemented with transferable skills training programmes and short stays/secondments at other highly competent academic and industrial partners from the fields of glycobiology and glycoimmunology. The training will secure a strong interdisciplinary education of the ESRs, and will guarantee the best background for a successful career in both academia and industry. Each academic ESR is further embedded in the local, most appropriate graduate/research school.
Network-wide training activities will include events and workshops as well as local courses and participation in (inter)national conferences.
- Training on CRC, cancer and glycomics/proteomics from the very beginning, in the form of lectures and workshops
- E-learning course on Glycobiology and Glycochemistry
- Workshop (Lectures and practicals) on current industrial methods for glycoanalysis
- Research and Quality Management workshops
- Communication skills workshops
- Data analysis workshops
- Business & Career workshops
- Doctoriales workshop, aiming at the preparation of the PhD student to integrate into company environment