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BCMolMed stands for Molecular Medicine for Bladder Cancer and it is a European Project funded by Marie Sklodowska-Curie Action.

 

Basics about Marie Sklodowska-Curie Action

Marie Sklodowska-Curie action is a programme that supports the development of scientists at different levels of their career in various research fields. Currently, Marie Sklodowska-Curie action is the main European Union source of founding, taking care of 25.000 PhD students. Among this programme, several funding opportunities exist including Individual Fellowships, Innovative Training Networks, Research and Innovative Staff Exchange and Co-founding of regional, national and international programmes.

 

BCMolMed Project is funded within the frame of International Training Network (ITN), which places particular emphasis on the collaboration between different working environments, including academia and industry. Especially for the Early Stare Researchers (PhD students), this multi-institutional collaboration provides with unique opportunities to gain experience in different research sectors and improve on various skills.

 

If you are further interested in Marie Sklodowska-Curie Action, we would like to recommend you to visit the official Webpage:

http://ec.europa.eu/research/mariecurieactions/

 

Summary of research cycle

The standard workflow for the scientific research is originated from the reviewing of existing literature to find and bridge the gaps in the existing knowledge. Based on above, a scientific hypothesis is generated and a study is designed to prove or not the hypothesis. While performing a study, a biomarker study in particular, several factors are considered, including: a) clinical/ disease context, b) selection of appropriate patients and control groups of individuals, c) selection of the appropriate statistical and analytical methodologies and d) selection of the biological material for discovery and intended implementation1. Followed by the experimental part of the workflow, the findings are evaluated in the biological context and biomarker performance is assessed in a large-scale multi-cohort study in the targeted population2.

 

 

(Adopted by Frantzi M, Bhat A, Latosinska A. Clinical proteomic biomarkers: relevantissues on study design & technical considerations in biomarker development. Clin Transl Med. 2014 Mar 29;3(1):7.)

 

Overview on BCMolMed Research

BCMolMed is a multidisciplinary project focusing on biomarker research for bladder cancer. In parallel, by employing the current state-of-the-art proteomics technologies, more knowledge is gained on molecular alterations and mechanisms during bladder cancer progression. The clinical relevance of the project is described in the section “General Public and Patients”.

 

BCMolMed utilize highly sophisticated Mass Spectrometry-based platforms, classical biochemical assays and systems biology approaches, in order to a) collect high dimensional -omics data, b) identify promising protein biomarkers for bladder cancer, c) integrate the new information with the existing knowledge towards building a molecular model of bladder cancer invasion. This workflow may notably facilitate the implementation of the novel biomarkers into clinical practice as well as likely lead to development of novel drug targets.

 

 

Why to study proteins?

Proteomics is the field of science that focuses on the global analysis of protein structures, functions and interactions. Proteins act as catalysts of biological processes and reflect the functional state of the cells. As such, changes at the protein (expression) level are often indicators of disease pathological conditions.

 

Proteomics studies in cancer research

Application of global proteomics analysis in the field of cancer research enable for:

  • better understanding of mechanisms underlying tumorigenesis and/ or associated processes,
  • studying interactions and signaling pathways between cancer and tumor environment,
  • development of molecular signatures for disease,
  • detection of putative targets for drugs,
  • development of clinically useful biomarkers

 

Technological platforms

BCMolMed project combines various research approaches aiming at improving on current medical practice in bladder cancer. For this purpose, we employ the latest technological achievements, such as mass spectrometry-based platforms (CE-MS, LC-MS/MS), classical biochemical assays (ELISA, IHC), transcriptomic analysis (mRNA sequencing), in vitro functional studies in cell lines, as well as bioinformatics integrative tools, in order to identify the most relevant protein changes in clinical samples and cell line models. All these changes are placed in the context of the already reported scientific information to connect the findings and discover potential drug targets. The overview on individual research projects  is provided below.

 

Project 1: Evaluation of association of known or suspected biomarkers with bladder cancer

The projects includes: a) the verification and assessment of currently known bladder cancer biomarkers in well powered studies using CE-MS, b) validation of the findings at the urine levels by ELISA and tissue levels using Immunohistochemistry and c) the in vivo investigation of the existing biomarkers in xenografts animal models (NOD/SCID mice). The biomarkers of interest are: Profilin-1, Zinc finger-335 (NIF-1), Histone H2B, Myeloblastin, specific fragments of Collagen, Fibrinogen, Uromodulin.

 

Project 2: New biomarkers: changes in ECM and secretome associated with bladder cancer

Existing data emphasize the role of extracellular matrix proteins in bladder cancer invasion. Therefore, the research project is focused on expanding the existing knowledge by collection of new –omics data from bladder cancer cell line models (approach focused on analysis of secreted proteins) and tumor biopsies. The project is comprised of the following parts: a) analysis of differentially expressed proteins in bladder cancer cell line models differ in metastatic potential and b) analysis of proteins associated with bladder cancer invasion in tissue samples.

 

Project 3: In silico modelling of bladder cancer cell invasion

There is a wide variety of publically available data on bladder cancer invasion. The aim of research project is the consolidation of existing data. In order to achieve this goal, three steps were taken: a) literature mining and data source integration, b) generation of protein-protein interaction networks involved in bladder cancer invasion and c) determination of pathways relevant to bladder cancer invasion.

 

Related scientific terms:

 

Proteomic biomarker - Single peptide or protein associated with specific condition, detectable in biological fluids or tissue.

 

Biomarker profile - Combination of individual peptide/ protein markers by established algorithm providing with the output associated with the specific condition.

 

MS-based platforms - Mass spectrometry-based analysis enables for detection and quantification of the proteins in the complex biological sample. The high complexity of the human proteome, which is increasing upon trypsin digestion, impose the need for pre-fractionation prior to MS analysis e.g. by using liquid chromatography (LC) or capillary electrophoresis (CE). Since the MS measures the mass over charge ratio of the ions moving in the electric field, in order for peptides to be visible by MS, the ionization is required. 

 

 

CE-MS– MS-based platforms utilized for the analysis of the low molecular weight proteome (peptidome)3. The peptide separation occurs in the capillary according to the charge and size. After the MS analysis, the peptides are defined by the CE migration time, signal intensity and molecular mass. However, CE-MS alone is not applicable for sequencing. CE-MS enables for a fast and reproducible analysis and it has been widely applied for studying the naturally occurring peptides in body fluids.

 

LC-MS/MS – Tandem mass spectrometry combines two mass analysers in one instrument in order to first select the ion from the complex mixture (MS1) and further fragment it (MS2) to obtain the information about the sequence. Fragment masses are used for the database search, when the comparison of theoretical and experimental fragmentation results leads to the peptide identification4. Afterwards, relative quantification may be performed by using spectral counting or intensity-based method.

 

References

1.             Mischak, H. et al. Recommendations for biomarker identification and qualification in clinical proteomics. Sci Transl Med 2, 46ps42 (2010).

2.         Frantzi, M., Bhat, A. & Latosinska, A. Clinical proteomic biomarkers: relevant issues on study design & technical considerations in   biomarker development. Clin Transl Med 3, 7 (2014).

3.         Stalmach, A., Albalat, A., Mullen, W. & Mischak, H. Recent advances in capillary electrophoresis coupled to mass spectrometry for clinical proteomic applications. Electrophoresis 34, 1452-64 (2013).

4.         Steen, H. & Mann, M. The ABC's (and XYZ's) of peptide sequencing. Nat Rev Mol Cell Biol 5, 699-711 (2004). 

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