Imaging Glioblastoma metabolism using mass spectrometry imaging

Glioblastoma (GB) is an inherently heterogenous and invasive primary brain tumour. Genetic and transcriptomic studies have attempted to classify GB into subtypes that can identify therapeutic vulnerabilities and predict survival, these include metabolic subtypes. An outstanding question and technical challenge is to visualize the metabolism of a tumour within its native microenvironment and understand to what extent its metabolism is driven by the microenvironment. Using isotope tracing and mass spectrometry imaging (MSI), I identified three metabolic signatures in patient GB tumours: glycolytic, oxidative and a mixed glycolytic/oxidative phenotype. These phenotypes do not correlate with microenvironmental characteristics such as proliferation rate, immune cell infiltration, hypoxia, or vascularisation. Growing cells outside the primary tumour as primary cell lines and then implanting them orthotopically into rodent brains did not change their metabolic phenotype. In addition, modulation of the microenvironment *in vitro* (including hypoxia, growth factors addition and immune signalling), did not alter these metabolic phenotypes suggesting that they represent cell intrinsic states. The three metabolic phenotypes showed differential drug sensitivity. One drug, MM315, an apelin receptor antagonist that is known to play a role in angiogenesis and differentiation of neural progenitor cells, significantly prolonged the survival of orthotopically implanted patient-derived xenografts and led to apoptosis of primary GB cells in culture. Taken together, the data suggests that metabolic imaging may be used clinically to identify tumour phenotypes and stratify patients for personalised therapy trials.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Tsyben, Anastasiya

Advisor dc:contributor.advisor

• Brindle, Kevin

• glioblastoma
• metabolism
• MSI

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f79d5508-c9fe-4675-b821-db325c181036/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0001-9659-3127

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/367593