A Systems Approach to Characterising Cancer Metabolism and Overcoming Therapeutic Resistance
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Embargo End Date
2026-09-26
ICR Authors
Authors
Kohli, M
Document Type
Thesis or Dissertation
Date
2026-03-26
Date Accepted
Abstract
Metabolic reprogramming is a recognised hallmark of cancer, yet systematic analyses of flux-level alterations across tumour types and
in therapy resistance contexts remains limited. Here we present two studies that focus on characterising tumour metabolic flux. In the
first study, we present a pan-cancer atlas of metabolic flux generated through genome-scale metabolic modelling and flux balance
analysis (FBA) of transcriptomic data from over 10,000 tumours across 28 cancer types from The Cancer Genome Atlas (TCGA). By
constructing and comparing metabolic models for tumours and their matched normal tissues, we identified both universal and tissuespecific
metabolic alterations. These included shared dependencies on pathways like bile acid metabolism and a unique reliance on de
novo purine synthesis in renal cancer. Further integration of enzyme constraints and nutrient diffusion limits allowed us to explore how
nutrient deprivation and other regulatory factors drive metabolic reprogramming, revealing crucial links between metabolic phenotypes,
transcription factor activity, and oncogenic mutations. Finally, to demonstrate the clinical relevance of our findings, machine learning
models leveraging fluxomic features accurately predicted patient survival, highlighting biotin uptake as a potential prognostic biomarker.
In the second study, we systematically characterise metabolic changes that occur as a result of endocrine therapy resistance. Using
flux balance analysis of clinical datasets alongside in vitro validation, we identified peroxisomal fatty acid oxidation (FAO) as a key
metabolic adaptation in resistant tumours. Resistant cell lines demonstrated increased FAO activity, enhanced lipid droplet
accumulation, and higher dependence on pyrimidine biosynthesis under nutrient stress. Pharmacological inhibition of peroxisomal FAO
disrupted redox balance, impaired nucleotide metabolism, and synergised with fulvestrant. These findings highlight metabolic rewiring
as a driver of resistance and reveal peroxisomal FAO as a tractable therapeutic vulnerability.
Together, these studies provide a comprehensive view of tumour metabolic flux, spanning both pan-cancer and therapy-resistance
contexts. By integrating computational modelling with experimental validation, we identify conserved and tissue-specific metabolic
dependencies, uncover novel links between regulatory programs and metabolism, and highlight clinically actionable vulnerabilities.
These include renal cancer’s reliance on purine synthesis and the dependence of endocrine-resistant breast cancers on peroxisomal
fatty acid oxidation.
Citation
2026
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Signalling Cancer Metab