MRC DTP in Precision Medicine

Mitochondrial Metabotyping to Identify Targetable Metabolic Vulnerabilities in PIK3CA-associated Disorders

Supervisors

Dr Thomas MacVicar, School of Cancer Sciences, University of Glasgow
Prof Robert Semple, Institute for Neuroscience and Cardiovascular Research, University of Edinburgh
Dr Ralitsa Madsen, MRC Protein Phosphorylation Unit, University of Dundee

Summary

Healthy tissue function features close metabolic cooperation among different cell types. Metabolic cooperation is hijacked in cancer and overgrowth diseases to supply energy and nutrients that support cell growth and spread. Mutations in the catalytic subunit of PI3K, encoded by PIK3CA, are among the most common mutations found in cancer and severe overgrowth syndromes known as PIK3CA-Related Overgrowth Spectrum (PROS). This project seeks to understand how mutations in PIK3CA reprogram mitochondria, which are the central metabolic hubs of the cell, and to investigate how metabolic communication between mutant cells and surrounding fat tissue can drive disease progression. A deeper understanding of mitochondrial dysfunction and niche metabolic vulnerabilities will provide future strategies for precise therapeutic intervention in PIK3CA mutant disease.

During this project, the student will use established stem cell models carrying hotspot PIK3CA mutations and map their metabolic profiles across cell types and with adipocyte co‑culture. The student will measure mitochondrial function and lipid metabolism using state-of-the-art techniques including metabolomics, isotope tracing, proteomics, and high‑resolution imaging. Furthermore, the student will be trained in integrative computational modelling to predict metabolic vulnerabilities and will test those with drug and CRISPR-based approaches.