Metabolism in haematological cancer cells

Eraslan, Zuhal (2021). Metabolism in haematological cancer cells. University of Birmingham. Ph.D.

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Abstract

Cancer cells exhibit a rewired metabolism to meet their specific energy needs for cell proliferation. Despite remarkable efforts to unravel how cancer cells reprogram their metabolism, characterization of the metabolic differences between the different subtypes of cancer has not been well performed. Haematological cancers can be divided into subtypes with significant implications for diagnosis and treatment.
The metabolic profiles of a panel of 18 haematological cancer cell lines representing acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), multiple myeloma (MM), Burkitt’s lymphoma (BL) and diffuse large B cell lymphoma (DLBCL) were characterised using an NMR approach. I found a notable widespread metabolic heterogeneity between haematological cancer subtypes, even though all haematological cancer cells showed a typical Warburg effect with lactate production. Intriguingly, MM cells were observed with a large amount of leucine uptake. The exploration of leucine metabolism using stable isotope tracer revealed that leucine is fully metabolised in MM cells and feeds the TCA cycle as well as sialic acid formation. Moreover, metabolic differences between BL and DLBCL were scrutinised, as these diseases tend to share similar morphological, immunophenotypic and genetic characteristics. Exogenous asparagine was found to regulate serine metabolism in BL cells. Furthermore, the combination of asparaginase (ASNase), a clinically used agent that depletes exogenous asparagine, with a PHGDH inhibitor (NCT503) had a synergistic effect on the viability in BL cells, exhibiting more decrease in cell viability as compared to those obtained from treatment of ASNase alone. Conversely, the combination of ASNase with NCT503 showed no synergistic effect on the viability of DLBCL cells, suggesting that the combination of ASNase with NCT503 is solely synergistic for BL.
Hence, NMR-based metabolite profiling has revealed how metabolism alters in haematological cancers. This thesis has highlighted and investigated metabolic dependencies and vulnerabilities in different haematological cancer which can be utilised for diagnostic and therapeutic purposes in future.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):