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Exploiting Glycosylation of Colorectal Cancer for the development of improved diagnostics and therapeutics

Periodic Reporting for period 2 - GlyCoCan (Exploiting Glycosylation of Colorectal Cancer for the development of improved diagnostics and therapeutics)

Reporting period: 2017-09-01 to 2019-08-31

Colorectal cancer (CRC) is a major health burden worldwide, with 1.8 million cases and an annual mortality of 880,000 worldwide (2018). Early detection is crucial, as the treatment is most efficient when administered in early stages. However, current screening methods are not optimal, they are invasive and often not accurate enough to detect CRC with certainty. Many research groups are looking for more CRC-specific markers to improve diagnosis and in particular early detection. Likewise, it is important to understand the mechanisms behind CRC onset, in order to develop novel treatments which can be personalized to provide the best cure for everyone.

In the search for new markers to detect CRC, to predict the survival of individual patients and to identify new treatment targets, the GlyCoCan consortium investigated a promising class of molecules, so far underappreciated in the clinics: carbohydrate chains, also referred as glycans. These glycans are attached to proteins and lipids. All our cells are densely covered with these molecules, and 50-70% of the proteins present in our blood are carrying glycan chains. Glycans are involved in probably any physiological process, including cell development. The glycan characteristics change depending on specific conditions in our body, and these changes can help to identify a disease. Furthermore altered glycosylation is an hallmark of pathological conditions such as cancer and contribute to disease mechanisms.

The GlyCoCan consortium performed research to understand i) which changes in glycan characteristics occur in CRC and ii) what impact these changes have on CRC development and other biological events in our body. For this, new techniques were developed which allowed to identify and characterize glycans as well as to study their functional roles. The GlyCoCan consortium combined excellent scientific research with high-quality training for 13 PhD students (ESRs) in three different disciplines: (1) Glycobiology, focussing on the general understanding and characterization of glycans in CRC; (2) Glyco-immunology, studying the role of glycans in immune responses in CRC; (3) Clinical glycomics, evaluating glycans as novel markers for diagnosis and prognosis of CRC.

More information on the project and people involved as well as descriptions of individual ESR project can be found on: https://glycocan.eu/.
The GlyCoCan project considerably advanced our knowledge on the glycosylation of CRC tumor tissues and cell lines. Likewise, effort was put into furthering glycoanalytical technology regarding throughput, sensitivity and analytical depth. N-glycans from colorectal cancer tissues were analyzed with mass spectrometry imaging providing novel insights into glycosylation signatures of the tumor as compared to the neighboring, largely unaffected colon epithelial tissues. Together with the analyses of N-glycans and O-glycans from CRC-derived cell lines, this provided indications for glycosylation fingerprints that are associated with de-differentiation or poor differentiation of CRC cells. Further studies are needed to unravel to which extent these glycosylation features are involved in inducing the cellular molecular switches associated with malignancy.

The GlyCoCan project provided insights into the role of glycans in immunological processes in CRC. In fact, specific glycan structures are recognized by glycan binding proteins and seem to contribute to a down regulation of the immune response, favouring the tumour development. This data is fundamental to better understand CRC mechanism of disease, as well as to pinpoint to novel signatures to stratify CRC patients for the application of immunotherapeutics. With respect to valorisation, monoclonal antibodies were developed that react with specific glycan signatures of CRC. These monoclonal antibodies are able to identify CRC tissues, cell lines, as well as CRC-derived proteins and have potential for diagnosis and targeted therapy. Further studies with larger sample cohorts and pre-clinical models are necessary to validate the added value of these antibodies in the clinics.

Notably, GlyCoCan revealed glycomic serum signatures that allow to discriminate between CRC patients and controls. Glycoproteins from human serum appeared to carry a glycosylation signature with potential for disease staging and prognosis and eventually treatment decisions. In an attempt to further improve the significance of these signatures we analysed the glycosylation of specific blood proteins including immunoglobulins and acute-phase proteins. These analyses allowed to pinpoint to specific glycan attachment sites on particular proteins that appear to be differentially glycosylated with CRC. More specifically, individual glycosylation signatures of each of the examined proteins (immunoglobulin A and G, haptoglobin) showed a potential as disease biomarker. Of note, next to N-glycosylation, also O-glycosylation of plasma proteins (namely immunoglobulin A) was associated with CRC. Further research into the validity of the newly discovered disease markers as well as into suitable detection technology will be needed to replicate these CRC glycosylation signatures and evaluate their clinical benefit.
The identification of CRC glycan signatures may allow in the future to better stratifying patients that benefit from current therapies. This together with glycan -targeting treatments relying on anti-glycan antibodies will contribute to so-called personalized medicine aiming to improve patient treatment, to spare patients from inefficient and costly treatments that often come with associated side-effects and to improve the rationale behind the drug administration at hospitals.

In addition to these CRC-centered discoveries, we expect that the development and optimization of new workflows for high-throughput glycosylation analysis of serum proteins (haptoglobin, immunoglobulin A and G, α1 acid glycoprotein, carcinoembryonic antigen) and the creation of a library of glycopeptide standards which were achieved through the GlyCoCan project will enable future work in the area of glycan biomarker discovery.

GlyCoCan results are disseminated via various channels to reach clinicians, patients as well as the biopharmaceutical industry. The website informs the public about the project aims and achievements (https://glycocan.eu/).
Scheme representing the work performed by the GlyCoCan consortium