Does peroxisome biogenesis regulate hypoxic triple negative breast cancer survival?

About the Project

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterised by the absence of targetable hormone receptors and poor prognosis. All solid tumours, including TNBC, contain regions of hypoxia (0.1-2% O2). Hypoxic tumour cells are highly resistant to chemotherapy and radiotherapy, driving relapse and disease progression. Targeting this therapy-resistant fraction is one of the most pressing unmet needs in breast cancer research.

Peroxisomes are multifunctional metabolic organelles present in virtually all eukaryotic cells, with established roles in fatty acid β-oxidation, ether phospholipid synthesis, redox homeostasis, and immune-regulatory lipid signalling. Their number, size, and protein composition are dynamically regulated in response to cellular stress, and all aspects of peroxisome biogenesis and proliferation are governed by 16 peroxisome biogenesis factor (PEX) genes. Despite this functional breadth, peroxisomes have been historically understudied relative to other metabolic organelles such as mitochondria, and their role in cancer biology remains poorly defined. Emerging evidence implicates peroxisomal activity in tumour progression, elevated ether phospholipid levels have been reported in multiple tumour types, and peroxisome-derived lipid mediators are known modulators of the tumour immune microenvironment, yet the peroxisome interactome, or composition, in human cancer has never been characterised, and PEX genes have not been systematically evaluated as therapeutic targets in TNBC. This represents a significant gap in our understanding of cancer metabolism and a potentially underexploited therapeutic opportunity.

This fully funded Breast Cancer Now studentship will provide the first comprehensive characterisation of the peroxisome proteome in hypoxic TNBC, determine whether PEX gene inhibition can selectively kill hypoxic cells and sensitise them to standard-of-care chemotherapy, and establish the relationship between PEX expression, hypoxic status, and immune infiltration in a syngeneic in vivo model of TNBC.

This project will employ a suite of state-of-the-art molecular, cellular, and in vivo approaches, including:

• TurboID-based proximity labelling proteomics
• siRNA-mediated gene knockdown
• CRISPR/Cas9 genome editing
• Clonogenic survival assays
• 3D spheroid culture
• RNA sequencing and bioinformatic analysis
• Confocal microscopy and immunofluorescence
• Immunohistochemistry
• Multiplex immunofluorescent staining
• Syngeneic orthotopic in vivo modelling

The project start date: 1st October 2026

Entry Requirements:

You must have, or expect to achieve, at least a 2:1 honours degree in an appropriate subject, including: cancer research, biomedical sciences. Candidates must have experience in relevant molecular biology techniques e.g.: mammalian cell culture, western blotting, RT-qPCR, immunofluorescence and transfection. A Masters degree (MSc or MRes) is advantageous but not essential.

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select (School of Clinical Dentistry) as the department.

Enquiries:

Interested candidates should in the first instance contact Dr Hannah Bolland, h.bolland@sheffield.ac.uk