The role of PHGDH in hypoxic adaptation and metabolic reprogramming

Thesis

Hypoxia is a common feature of solid tumours and is associated with poor prognosis and resistance to therapy. Attempts to therapeutically target hypoxic tumour cells have shown limited clinical success. This thesis investigates the role of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine synthesis pathway (SSP), in hypoxic adaptation and response to radiotherapy. PHGDH expression is induced under severe hypoxia (<0.1% O2). This induction is driven by combined HIF-1 and PERK-ATF4 signalling, linking oxygen sensing with cellular stress responses.

Loss of PHGDH was demonstrated to result in substantial metabolic rewiring. Increased glycolytic flux and lactate production were observed, alongside enhanced HIF-1 signalling. PHGDH-deficient cells showed improved survival and sustained proliferation under hypoxic conditions. Targeting PHGDH alone, therefore, did not impair adaptation to hypoxia. We demonstrated that the effect of PHGDH loss on radiosensitivity depends on extracellular serine availability. No radiosensitisation was observed under standard or physiological conditions. In contrast, complete serine deprivation resulted in significant radiosensitisation in both normoxia and hypoxia. Reduced glutathione (GSH) levels accompanied this effect, supporting a role for redox imbalance in radiation response. Targeting the SSP is therefore highly context-dependent and influenced by nutrient availability, which is often overlooked in experimental design. PHGDH also exhibits non-canonical behaviour in hypoxia, including nuclear localisation and a potential association with R-loop biology, although this requires further investigation.

Overall, PHGDH functions as a hypoxia-regulated metabolic enzyme with limited utility as a standalone therapeutic target. Moreover, our findings highlight the importance of metabolic context in determining the need to account for tumour microenvironmental conditions in therapeutic strategies.

Authors: Petrosyan, E

• DOI: 10.5287/ora-9re26q6b9
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: tumour microenvironment; hypoxic adaptation; serine synthesis pathway; HIF-1; TME; cancer; PHGDH; hypoxia; metabolic reprogramming; metabolism; serine
• Subjects: Metabolism; Oncology; Cancer