Northwood
Project with
The Madsen Lab is dedicated to a systems understanding of PI3K signalling plasticity, inspired by observations from human disorders such as cancer and PIK3CA-related overgrowth spectrum (PROS) 1,2. Over the last five years, with support from Wellcome funding, we uncovered previously unappreciated allele dose-dependent effects of PIK3CA mutations in human pluripotent stem cells and cancer 3–5. Recently, we also developed a versatile single-cell experimental framework for studies of quantitative, PI3K-dependent information transfer, demonstrating for the first time that the most frequent oncogenic PIK3CA mutation, PIK3CAH1047R, is not a simple ON switch of the pathway as commonly assumed. Instead, PIK3CAH1047R corrupts the ability of cells to resolve the identity of different growth factors, akin to “blurred” signal transfer 6. Supported by a UKRI Future Leaders Fellowship, the Madsen Lab now seeks to develop context-dependent and therapeutically predictive PI3K signalling maps7,8 by leveraging state-of-the-art quantitative technologies (mass spectrometry, mass cytometry, scRNAseq, live-cell imaging), computational modelling and novel experimental systems for controllable PIK3CAmutant expression in human iPSCs and their differentiated derivatives9.
As part of this collective effort, the lab offers a PhD project with the following objectives: 1) mapping the PIK3CA mutant-specific interactome across biological systems (iPSCs, endothelial cells, cancer models), at baseline and in response to growth factor-specific stimulation; 2) causal inferences using the resulting network models10 to identify therapeutically-targetable mechanisms of PIK3CA mutant-specific signal transfer; 3) experimental validation of predicted “signal-correcting” interventions in disease-relevant models (PROS and cancer).
If an interdisciplinary scientific puzzle does not put you off, if you are unafraid of quantitative biology, if you are kind, well-organised and incurably curious, then you are the PhD student we are looking for to join our lab. You will gain highly competitive skills in single-cell biology, quantitative signalling, pluripotent stem cell culture, bioinformatic analyses and computational modelling of signalling networks. You will be part of existing collaborations between the Madsen group and partners in the UK and the U.S., including Prof. Robert Semple (University of Edinburgh), Prof. Owen Sansom (CRUK Scotland Institute) and Prof. Andre Levchenko (Yale Systems Biology Institute).
By joining a relatively young group, you will also benefit from daily supervision and hands-on training by the PI as well as a modern and inclusive approach to research culture: we are committed to excellence underpinned by research integrity, care and respect.
1. Madsen, R. R., Vanhaesebroeck, B. & Semple, R. K. Cancer-Associated PIK3CA Mutations in Overgrowth Disorders. Trends in Molecular Medicine 24, 856–870 (2018).
2. Madsen, R. R. & Semple, R. K. PIK3CA-related overgrowth: silver bullets from the cancer arsenal? Trends in Molecular Medicine 28, 255–257 (2022).
3. Madsen, R. R. et al. Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner. Proceedings of the National Academy of Sciences 116, 8380–8389 (2019).
4. Madsen, R. R. et al. Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. PLOS Genetics 17, e1009876 (2021).
5. Madsen, R. R. et al. NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells. Disease Models & Mechanisms 14, dmm.048298 (2021).
6. Madsen, R. R. et al. Oncogenic PIK3CA corrupts growth factor signaling specificity. 2023.12.23.573207 Preprint at https://doi.org/10.1101/2023.12.23.573207 (2023).
7. Madsen, R. R. & Vanhaesebroeck, B. Cracking the context-specific PI3K signaling code. Science Signaling 13, eaay2940 (2020).
8. Madsen, R. R. & Toker, A. PI3K signaling through a biochemical systems lens. Journal of Biological Chemistry 299, 105224 (2023).
9. Ang, L. T. et al. Generating human artery and vein cells from pluripotent stem cells highlights the arterial tropism of Nipah and Hendra viruses. Cell 185, 2523-2541.e30 (2022).
10. Erickson, E. C. et al. Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation. Science Signaling 17, eadf2670 (2024).