TRACT

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TRACT

TRACT - Training in Cancer Mechanisms and Therapeutics
TRACT
Marie Skłodowska-Curie Action
TRACT supports eleven PhD Fellows to complete research projects in the three critical areas: biomarker discovery, molecular resistance mechanisms and metabolic transformation mechanisms. This will allow for the discovery of novel insights into the molecular and cellular basis of oral and oesophageal cancer and generate new diagnostic tools and therapeutics that will improve patient response and survival.


TRACT Marie Skłodowska-Curie PhD Fellowship with OROBOROS INSTRUMENTS / Medical University Innsbruck

  • 2017-03-01 Anja Bufe starts her PhD project with OROBOROS INSTRUMENTS at the Medical University of Innsbruck, within the Marie Skłodowska-Curie Innovative Training Network TRACT.

WP3/ESR10: Metabolic transformation

  • High-resolution respirometry to assay real time bioenergetics and metabolism in oral cancer cells
  • Metabolic profiles of normal, dysplastic and cancerous oral cells
  • Comparison of oxygen consumption and extracellular proton flux, as metrics of metabolic flux in different cell types under normoxic and hypoxic conditions; correlate with chemotherapy sensitivity
  • Identify differential novel drug targets in the cancer cells
TRACT will examine metabolic transformation mechanisms in OOC with the aim of identifying new drug targets for future therapeutic development. Metabolic transformation is a universal property of tumour formation and is a rich source of targets for development of therapeutic interventions. ESR 10 (Oroboros recruit; TCD secondment) will further characterise the bioenergetic and metabolic differences in normal, dysplastic and cancerous oral cancer cells using the OROBOROS O2k-MultiSensor system. This approach will identify differential novel drug targets and means to enhance the chemotherapeutic sensitivity of cancer cells. Factors that control mitochondrial dynamics in cancer cells have also emerged as possible therapeutic targets.
The dynamic structure of the mitochondria in mammalian cells is defined by the opposing forces of fission and fusion, but the regulation of these mitochondrial processes is poorly understood. This is an emerging area in cancer research where cutting-edge imaging technologies are merging with molecular and cellular biology techniques. Pilot studies performed by Porter in TCD have identified a key molecule involved in controlling mitochondrial abundance (namely SIRT3) as a determinant of drug resistance in some solid cancers. ESR 11 (TCD recruit; Oroboros secondment) will establish the relationship between mitochondrial abundance, morphology, functional proteins involved in mitochondrial dynamics and metabolic differences in normal, dysplastic and oral cancer cells. This new knowledge will lead to the identification of novel therapeutic targets.
  • Planned secondment: TCD (Porter, 9 months from M13) - measure metabolic flux through (a) glycolysis, (b) pentose phosphate pathway and (c) glutaminolysis using 2H/13C NMR.


Training in mitochondrial and cellular respiratory physiology

  • Project month 12
  • Duration: 3 days
Oroboros will provide O2k-Workshops to TRACT ESRs on use of the Oxygraph-2k respirometer to measure oxygen consumption, transmembrane potential differences using TPP-electrodes and fluorescence sensitive sensors to determine hydrogen peroxide production (Amplex red), membrane potential (Safranin, TMRM), ATP production (Mg green) or Ca2+ (Ca green).
The non-academic sector has a key role in TRACT in delivery of both the research/training elements of the programme and overall project oversight.

Relevant publications

  • Harrison DK, Fasching M, Fontana-Ayoub M, Gnaiger E (2015) Cytochrome redox states and respiratory control in mouse and beef heart mitochondria at steady-state levels of hypoxia. J Appl Physiol 119:1210-8. - »Bioblast link«
  • Gnaiger E (2014) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 4th ed. Mitochondr Physiol Network 19.12. OROBOROS MiPNet Publications, Innsbruck:80 pp. - »Bioblast link«
  • Krumschnabel G, Eigentler A, Fasching M, Gnaiger E (2014) Use of safranin for the assessment of mitochondrial membrane potential by high-resolution respirometry and fluorometry. Methods Enzymol 542:163-81. - »Bioblast link«
  • Gnaiger E, Boushel R, Søndergaard H, Munch-Andersen T, Damsgaard R, Hagen C, Díez-Sánchez C, Ara I, Wright-Paradis C, Schrauwen P, Hesselink M, Calbet JAL, Christiansen M, Helge JW, Saltin B (2015) Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and caucasians in the arctic winter. Scand J Med Sci Sports 25 (Suppl 4):126–34. - »Bioblast link«
  • Kristiansen G, Hu J, Wichmann D, Stiehl DP, Rose M, Gerhardt J, Bohnert A, ten Haaf A, Moch H, Raleigh J, Varia MA, Subarsky P, Scandurra FM, Gnaiger E, Gleixner E, Bicker A, Gassmann M, Hankeln T, Dahl E, Gorr TA (2011) Endogenous myoglobin in breast cancer is hypoxia-inducible by alternate transcription and functions to impair mitochondrial activity: a role in tumor suppression? J Biol Chem 286:43417-28. - »Bioblast link«
  • Eberhart K, Rainer J, Bindreither D, Ritter I, Gnaiger E, Kofler R, Oefner PJ, Renner K (2011) Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia. Biochim Biophys Acta 1807:719-25. - »Bioblast link«
  • Scandurra FM, Gnaiger E (2010) Cell respiration under hypoxia: facts and artefacts in mitochondrial oxygen kinetics. Adv Exp Med Biol 662:7-25. - »Bioblast link«


TRACT: Call H2020-MSCA-ITN-2016

In 2012, 8.2 million people worldwide died of cancer, of which 5.3% or over half a million deaths were accounted for by oral and oesophageal cancer (OOC)

The European community requires early stage researchers (ESRs) trained in next-generation technologies for improved detection and treatment of oral and oesophageal cancers. The number of oral cancers diagnosed in the EU has increased by over 75% in the last 30 years, with long-term survival rates of only 50%. This is typically due to the late diagnosis of the disease and resistance to current therapies. Through the collaborative expertise of clinicians, biochemists, immunologists, and chemists TRACT will enable ESRs to discover novel insights into the molecular and cellular basis of these cancers and generate new diagnostic tools and therapeutics that improve patient response and survival. Each Institution brings unique but complementary expertise in cancer metabolism, metabolomics, high-resolution imaging, biomarker identification, computational modelling, medicinal chemistry, target validation, drug development and translational medicine. Industrial placements in five European countries will ensure ESRs receive specialised training in the development of next-generation technologies in such areas as whole genome sequencing, CRISPR technology, drug screening, exosome isolation and analysis, cancer imaging, metabolism and metabolite analysis in addition to the unique employment experience of working in the private sector. Courses in commercialisation, project management and presentation skills will ensure ESRs will have the ability to present their results to the entire cross-section of the European community, through public engagement.


Objectives

TRACT will provide ESRs with exposure to a collaborative network of European academic and industrial experts working in the complementary domains of cancer metabolism, metabolomics, high-resolution imaging, bioinformatics, biomarker identification, computational modelling, medicinal chemistry, target validation, drug development, nanotechnology and translational medicine. Although there are many researchers working on OOC in the relevant domains listed above, there is a lack of integration between domains - through a programme of integrative training and research, TRACT will bring together relevant domains to deliver better diagnostics and therapeutics for OOC with the overall aim of improving patient response and survival.


TRACT will deliver a cohort of internationally mobile cancer researchers with interdisciplinary skills who will have enhanced career prospects and be in a position to have an impact on the European and global research stage by providing new technologies that can drive entrepreneurship into the European economy and improved diagnostics and treatment options for cancer patients in Europe and beyond.


The overall aim of the research programme is to integrate basic and applied research in three related themes in order to deliver new diagnostic & prognostic tools and therapeutic approaches for patients with OOC.
During the project, TRACT ESRs will undertake novel research to:
1) Determine novel biomarkers at the protein, glycan and molecular level to enable early detection of OOC and to predict patient response to therapy.
2) Uncover the molecular basis of drug resistance in OOC leading to the identification of new drug targets and the development of novel cancer therapeutics.
3) Enhance knowledge of metabolic transformation in OOC leading to the identification of novel targets for therapeutic intervention.
TRACT Diagnosis and therapy


TRACT Marie Skłodowska-Curie PhD Fellowships

TRACT is an international, inter-sectoral, multi-disciplinary project providing Marie Skłodowska-Curie PhD Fellowships to early stage researchers (ESRs) with the potential to become the leaders of tomorrow in cancer research.
Total applications received: 150
Countries represented: 44
Application profiles: 34% were EU, 4% are candidate EU countries and 62% are non-EU applicants.
Gender balance: 59% women, 41 % men.
Appointed PhD students who will be starting in March: 11


Coordinator

TRACT project manager:
Catherine McPartlin
Trinity College Dublin - IE
MCPARTLC@tcd.ie
TRACT project coordinator:
Dr Daniela Zisterer
Trinity College Dublin - IE
OROBOROS project manager:
Mag. Verena Laner


Project partners


Trinity College Dublin link=http://wiki.oroboros.at/index.php/OROBOROS_INSTRUMENTS OROBOROS Universitat de València Università degli studi di Siena The Queen's University of Belfast


Further partner organisations

Agilent Technologies Almac Diagnostics Andor Technology Fraunhofer Gesellschaft Horn international - Exosomics Siena S.p.A. National Institute for Bioprocessing Research and Training Opsona Therapeutics