Real-time metabolic flux in chronic lymphocytic leukaemia cells adapting to the hypoxic niche

Koczuła, Katarzyna Malgorzata (2015). Real-time metabolic flux in chronic lymphocytic leukaemia cells adapting to the hypoxic niche. University of Birmingham. Ph.D.

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Abstract

Although knowledge of metabolic adaptations in cancer has increased dramatically, little is known about the spontaneous adoptive adaptations of cancer cells to changing conditions in the body. This is particularly important for chronic lymphocytic leukaemia (CLL) cells which continually circulate between different microenvironments in the blood, bone marrow and lymph nodes.
To study such metabolic adaptations, a nuclear magnetic resonance (NMR) based approach; capable of monitoring real-time metabolism in primary CLL cells was developed. Using this setup, this thesis demonstrates fast, reversible metabolic plasticity in CLL cells during transition from normoxic to hypoxic conditions, associated with elevated HIF-1α dependent glycolysis. This work also demonstrates differential utilisation of pyruvate in oxygenated and hypoxic conditions where in the latter, pyruvate was actively transported into CLL cells to protect against oxidative stress. Moreover, real-time NMR experiments provided initial evidence that CLL metabolism in hypoxia correlates with stage of disease, adding significant relevance of our method for patient stratification. Additionally, to further investigate alterations between normoxic and hypoxic metabolism, Metabolic Flux Analysis (MFA) was carried out using primary CLL cell extracts, revealing modifications in pyruvate carboxylase (PC) activity and the pentose phosphate pathway (PPP).
Despite the recent advent of promising new agents, CLL currently remains incurable and new therapeutic approaches are required. Understanding CLL cell adaptation to changing oxygen availability will permit the development of therapies that interfere with disease aetiology. This study makes several significant contributions towards this goal. Moreover, the findings may be relevant to all migratory cancer cells, and may have importance for the development of strategies to prevent cancer metastasis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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