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GlyCoCan Report Summary

Project ID: 676421
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - GlyCoCan (Exploiting Glycosylation of Colorectal Cancer for the development of improved diagnostics and therapeutics)

Reporting period: 2015-09-01 to 2017-08-31

Summary of the context and overall objectives of the project

Colorectal cancer (CRC) remains a major cancer burden worldwide, with 1.4 million cases and an annual mortality of 700,000 worldwide (2012) . Early detection is crucial, as the treatment is most efficient when administered in early stages. However, current screening methods are not optimal: invasive and often not accurate enough to detect CRC with certainty. Many research groups are investigating more CRC-specific markers to improve the detection of this particular type of cancer. In this line of research, it is also important to understand the mechanisms behind CRC onset, in order to develop novel treatments which can be individualized to provide the best cure for everyone.
In this search of new markers to detect CRC as well as to predict the survival of individual patients and to identify new treatment targets, the GlyCoCan consortium is investigating a promising class of molecules, so far underappreciated in the clinics: glycans. These carbohydrates are attached to proteins and lipids and our cells are covered with a forest of these molecules, while 50-70% of the proteins present in our blood are carrying them. Glycans are involved in many processes in our bodies, including cancer development. Furthermore, the glycan characteristics change depending on specific conditions in our body, which can help to identify a disease.
Our aim within the GlyCoCan consortium is 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, we need to develop new techniques which allow us to identify and characterize glycans as well as to study their functional roles. The GlyCoCan consortium combines excellent scientific research with high-quality transferable-skill training for 13 PhD students (ESRs) in three different disciplines: Glycobiology (WP1; General understanding and characterization of glycans in CRC), Glyco-immunology (WP2; the role of glycans in immune responses in CRC) and Clinical Application (WP3; evaluation of glycans as novel markers for diagnosis and prognosis of CRC). We expect to increase awareness of the importance of glycans for human health as well as the understanding of glycan-related mechanisms in CRC, with the ultimate goal of finding improved diagnostic and prognostic biomarkers and pave the way for novel therapeutic targets, while training highly skilled ESRs with multi-disciplinary and inter-sectorial expertise. While most methods have been set-up in the first period of the project, characterizations and functional studies are ongoing and will be the focus of the remaining period.
More information on the project and people involved as well as descriptions of individual ESR project can be found on:

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In WP1 ‘Glycobiology’, methods were developed for the extraction, purification and analysis of N- and O-glycans by mass spectrometry. 300 tissue samples from patients with colon and rectal cancer and 48 human and mouse colorectal cancer (CRC) cell lines were collected within the GlycoCan consortium, including newly generated human primary cell cultures. While most cell lines have been characterized at glycomic (and other -omic) level, the analysis of tissues is ongoing. In addition to wildtype cell lines, new glyco-engineered CRC cell lines, with absent or overexpressed relevant glycan structures, were generated to study functional roles of glycosylation. Next to in-depth phenotypic characterizations, functional assays (growth ability, invasion and migration, epithelial to mesenchymal transition) have been performed in order to understand glycan-related mechanisms in CRC and will be further expanded. In addition, glycome dynamic experiments in cell lines using novel chemical reporters are currently ongoing to study the link between the glucose metabolism and CRC.
In WP2 ‘Glyco-immunology’, the role of glycosylation in immune responses within CRC is investigated, in particular how glycosylation can skew immune cells, including immunosuppression. Assays to assess C-type-lectin-mediated immunosuppression in CRC have now been established and the recognition of glyco-variant mouse CRC cell lines was evaluated by immunomodulatory C-type lectins expressed on immune cells. A syngeneic pre-clinical orthotopic mouse model has been developed, where CRC cells are implanted at the location of the corresponding tumor type. Using this orthotopic mouse model of CRC, the immune response can be studied with closer resemblance to the situation in humans, as compared to models with subcutaneous injections.
In WP3 ‘Clinical Application’, glycans are being evaluated as novel markers for diagnosis and prognosis of CRC. First results on IgG and total serum N-glycan profiling have been achieved and show promising results. A UPLC approach to evaluate IgG N-glycans in CRC cases and controls showed the potential of IgG N-glycans in differentiation of cases from controls. Using a mass spectrometry approach to evaluate released N-glycans from serum of CRC cases and controls showed the potential of serum N-glycans to differentiate cases from controls, and even stronger potential to associate with survival (prognostic biomarker). Next, the evaluation of haptoglobin, IgA, α1-acid-glycoprotein and carcinoembryonic antigen glycosylation from blood as diagnostic and/or prognostic marker for CRC will be performed. WP3 focuses as well on the generation of synthetic N-glycopeptides to be included as standards to increase the robustness of mass spectrometric analysis.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In all work packages novel glyco-analytical methods have been developed or optimized and will be extensively applied in the coming period. The method development forms the basis for ongoing and future studies within and beyond GlyCoCan. The developed techniques will be used and contribute to advance the understanding of CRC cancer progression and the identification of novel biomarkers, mechanisms and treatment targets, to meet current and expectedly fast growing needs of the European Health Economy. The acquired skills and methods are sorely needed in the biotechnological industry as well as in clinical research and can be applied beyond the objectives of the GlyCoCan training program.
The development of novel, specific antibodies against cancer-related glycan epitopes will not only support the research, but also the translation of glycomic markers into the clinic since their application can be envisioned in diagnosis as well as in therapy.
Other challenges in the clinics are early diagnosis, patient stratification and monitoring. Preliminary results on total serum and IgG N-glycome analysis in CRC case-control studies showed differences between CRC cases and healthy controls. Moreover, a classification rule showed prognostic value for several N-glycan traits. These glycomic markers as well as other ones emerging from GlyCoCan research will be evaluated for their use in patient stratification.
Constant dissemination to increase visibility of the GlyCoCan training program ensures close contacts with industry (commercialization) and clinicians (end-users, contact to patients) and informs the public about progresses and developments (

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