Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - HaemMetabolome (Deciphering the Metabolism of Haematological Cancers)

Teaser

HaemMetabolome was established to train 10 Early Stage Researchers in the field of experimental haematological cancer research and metabolism. This is carried out in the context of a Joint Doctorate scheme where each fellow is supervised and carries out research at two...

Summary

HaemMetabolome was established to train 10 Early Stage Researchers in the field of experimental haematological cancer research and metabolism. This is carried out in the context of a Joint Doctorate scheme where each fellow is supervised and carries out research at two different sites.

The objectives of the project are to provide research training in the study of metabolic mechanisms associated with cancer-specific metabolic features, the characterisation of key metabolism regulators, studying the effect of drugs on specific metabolic mechanisms and the use of computational approaches to integrate different data-sets to allow predictions of drug interactions, and markers for personalised treatment.

The objectives for ESRs working on HaemMetabolome are to characterise the metabolism of different haematological cancer cell lines and primary patient cells using nuclear magnetic resonance (NMR) and mass spectrometry (MS) in order to understand the mechanism of metabolic regulation in haematological cancers; to link metabolic profiles to the effect of specific metabolic regulators; and to look at the effect of drugs on these cells.

The Training objectives include: to build a career in outstanding areas of biology and biomedicine taught by leading international scientists in state-of-the art infrastructures, which covers a portfolio of interdisciplinary techniques; to develop skills in a wide range of techniques and to gain direct experience of interaction across disciplines and sectors; to produce researchers with excellent transferrable skills, able to transform abstract ideas into influential outcomes; to create an active, long-term network of young researchers who will help Europe shape the future of bioanalytical and biomedical research; to cascade expertise and spread good practice throughout Europe and delivering future leading researchers for Europe in interconnected fields of research.

Work performed

\"The work of the HaemMetabolome project has focussed on the key scientific and training objectives. Fellows have undertaken initial work on their research projects; the work undertaken and results obtained so far are described below.

Analysis of AML cell lines by NMR and MS using cell extracts and real-time NMR has been carried out, and the effects of drug treatments measured. A multi-omics approach has been developed with proteomics for AML cell lines grown for a longer time under low-oxygen conditions.

Established AML models for FLT3 mutations, for studying the effects of the mutations and inhibitors on cell metabolism

The AML THP-1 cell line was used to examine the role of TKTL1 under normoxia and hypoxia; metabolic profiles were linked to genetic changes using GSEA and GSMM tools.

CLL cell lines and CLL cells were characterised using different NMR approaches along with the effect of drugs that inhibit ATM, which is involved in DNA repair.

CML cell lines resistant to Imatinib and Hydroxyurea have been generated in order to characterise the metabolic control of drug resistance.

Different computational approaches were established in order to combine metabolism and genetic data. Initial tests focussed on Burkitt’s lymphoma cell lines.

Training objectives were addressed by activities on a local and network level. All fellows received training in different technologies; this includes secondment to their partner University within the joint-doctorate scheme. Training undertaken by the fellows includes cell biology and analytical techniques, along with training in computational analysis of data sets.

In January 2017, HaemMetabolome held the first project meeting in Barcelona; at this meeting, the fellows were introduced to the topics of assays in biological systems; technologies for measuring metabolomics and metabolic flux and technologies used for drug screening. Fellows also had the chance to develop their presentation skills by presenting their projects at the meeting.

To date, HaemMetabolome fellows have presented their research at meetings in their institutions, and presented several posters at international conferences, including at the “4th International Conference on Acute Myeloid Leukaemia \"\"Molecular and Translational\"\": Advances in Biology and Treatment” and at the 8th Mildred-Scheel Cancer Conference, Germany.

The project’s mid-term review meeting was held on the 13th September 2017 in Brussels, and was attended by all the Beneficiaries, Fellows and the REA Project Officer. Discussions held at the meeting provided useful feedback on both the science and management of the project, which will benefit all in the second half of the project.
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Final results

The collaborative nature of HaemMetabolome will drive forward research in this area, by generating a better understanding of the haematological cancers by bringing together different research fields.
• By using different analytical approaches to study metabolism in real-time by NMR, using tracer based metabolic flux analysis by NMR and using MS based metabolic analysis.
• Lentiviral shRNA vectors were used to create mutations in AML cell lines to understand the role of metabolism in leukaemia and cell survival.
• A low-oxygen environment was established for AML cell cultures to reflect the conditions AML cells grow in vivo, and to use proteomic and metabolomics to study these cells.
• Use AML cells to characterise the effect of inhibition on FLT3.
• Measure at the effect of hypoxia over longer time periods to study the effect this causes on a proteomic level.
• Study the effect of resistance against drugs including imatinib, hydroxyurea, AraC, and doxorubicin on the metabolism of AML cell lines.
• Determine the effect on cell metabolism in CLL cells with ATM and P53 mutations, using different experimental NMR approaches.
• Generation of knock down of TKTL1 and knockout of TET2 in leukaemia malignancies to study the down-stream metabolic effects.
• Computational tools have been established to analyse metabolic changes in the context of genetic and metabolic profiles.

Potential impact
HaemMetabolome creates impact by integration of the latest technologies that can determine the regulation and interactions of metabolic networks providing greater understanding behind haematological cancers, which will potentially lead to more effective treatments, diagnosis and better prognosis. It also combines a range of cutting-edge tools to analyse metabolism in challenging cellular environments, and by linking metabolic analysis to genetic profiles using computational approaches. HaemMetabolome links metabolic changes to the function of key metabolic regulators by knocking down proteins, by growing cells under specific low-oxygen conditions and by looking at the effect of inhibitors and drugs.

Website & more info

More info: http://haemmetabolome-itn.eu.