Overview
The Madsen Lab uses quantitative systems biology approaches to understand how cellular context shapes the output of oncogenic PIK3CA activation — with the ultimate goal of developing novel state-gating therapeutic strategies.
Our philosophy is rooted in information theory: to repair a broken signalling network, one must first understand how that network processes information in the normal state. As we describe to patient communities, fixing a PIK3CA-mutant cell is akin to repairing a broken radio — you need to understand the system before you can fix it.
Research Questions
1. How does oncogenic PIK3CA corrupt the PI3K signalling code?
Class IA PI3Ks are central transducers of growth factor signalling. The p110α catalytic subunit, encoded by PIK3CA, is among the most frequently mutated genes in human cancer, with activating mutations found across breast, endometrial, and colorectal cancers, as well as in overgrowth disorders such as PROS (PIK3CA-Related Overgrowth Spectrum).
We are interested in understanding at a quantitative level how disease-associated, activating mutations in p110α change the information-processing properties of the PI3K network — moving beyond simple “more or less activity” towards a systems-level understanding of how signalling logic is altered.
2. How does cellular context shape oncogenic PI3K output?
The same PIK3CA mutation can drive very different biological outcomes depending on the cell type in which it occurs. A mutation that promotes proliferation in one context may drive differentiation defects or metabolic reprogramming in another.
We use iPSC-derived cellular models and primary cell systems to systematically probe how cell state, lineage identity, and microenvironmental context determine the biological consequences of oncogenic PI3K activation.
3. Can we exploit context-dependent vulnerabilities therapeutically?
Understanding why the same mutation has different consequences in different contexts opens the door to state-gating: therapeutic strategies that exploit the fact that only certain cellular states are vulnerable to a given drug or intervention.
This is particularly exciting in the context of PROS, where mosaic activating PIK3CA mutations drive tissue overgrowth — and where selective targeting of affected cell states could achieve therapeutic benefit while minimising off-target toxicity.
Approaches & Technologies
We combine wet-lab and computational approaches, including:
- Single-cell quantification of the cellular transcriptome and signalling activity as a function of time
- iPSC-derived cellular models to study context-dependent PI3K signalling across relevant cell types
- Genetic engineering for precise PIK3CA mutations knock-in, installation of barcodes and inducible genetic perturbations
- Computational modelling of signalling network dynamics and gene regulatory network states
Funding
The Madsen Lab’s primary funding is from a UKRI Future Leaders Fellowship (Round 8), awarded to Dr. Ralitsa Madsen in November 2024. The fellowship supports research into mapping the context-dependent PI3K signalling code in health and disease, and contributes to the development of state-gating therapies.
Patient & Public Involvement
We actively engage with the PROS patient community, recognising that their lived experience of PIK3CA-related disease is invaluable for shaping the direction of our research. We are committed to communicating our findings in accessible language and to incorporating patient perspectives into our scientific priorities.