Dr Ralitsa Madsen - Cell State Control of Oncogenic Signalling
Introduction
The Madsen Lab is dedicated to a systems understanding of signalling plasticity within the growth-promoting phosphoinositide 3-kinase (PI3K) signalling pathway. Our work is inspired directly by observations from human disorders such as cancer and PIK3CA-related overgrowth spectrum (PROS). Over the last five years, we uncovered previously unappreciated allele dose-dependent effects of PIK3CA mutations in human pluripotent stem cells and cancer. 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. Supported by a UKRI Future Leaders Fellowship and CRUK funding, we now seek to develop context-dependent and therapeutically predictive PI3K signalling maps by leveraging state-of-the-art quantitative technologies (mass cytometry, scRNAseq, live-cell imaging), computational modelling and novel experimental systems for controllable expression of pathological PIK3CA variants in disease-relevant contexts.
EmailLab Report
Key Publications
*Corresponding author
Madsen RR*, Le Marois A, Mruk O, Voliotis M, Yin S, Sufi J, Qin X, Zhao SJ, Gorczynska J, Morelli D, Davidson L, Sahai E, Korolchuk VI, Tape CJ, Vanhaesebroeck B. Oncogenic PIK3CA corrupts growth factor signaling specificity. Molecular Systems Biology. 2024; 21:126-157.
Madsen RR*, Toker A*. PI3K signaling through a biochemical systems lens. Journal of Biological Chemistry. 2023; 299(10), 105224.
Erickson EC, You I, Perry G, Dugourd A, Donovan K, Ros S, Moss J, Ziegler R, Williamson S, Crafter C, Johannes J, Barry S, Fischer E, Gray N, Madsen RR*, Toker A*. Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation. Science Signaling. 2024;17(825):eadf2670.
Madsen RR*, Erickson EC, Rueda OM, Robin X, Caldas C, Toker A, Semple RK, Vanhaesebroeck B. Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.PLOS Genetics. 2021;17, e1009876.
Madsen RR*. PI3K in stemness regulation: from development to cancer. Biochemical Society Transactions. 2020;48:301-315.
Madsen RR*. Vanhaesebroeck B.* Cracking the context-specific PI3K signaling code. Science Signaling 2020, Jan 7; 13, eaay2940.
Biography
Education and qualifications
2018: PhD Metabolic and Cardiovascular Disease, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge
2014: MPhil Medical Science, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge
2013: BSc Molecular Biomedicine, University of Copenhagen
Appointments
2026-present: UKRI Future Leaders Fellow, CRUK Scotland Institute & University of Glasgow
2024-2026: UKRI Future Leaders Fellow, MRC-PPU, University of Dundee
2020-2024: Sir Henry Wellcome Fellow,
- Principal Investigator, MRC-PPU, University of Dundee (04.2024-11.2024)
- Independent Investigator, MRC-PPU, University of Dundee (05.2023-03.2024)
- Postdoctoral Researcher, UCL Cancer Institute (12.2020-04.2023)
2019-2020: Postdoctoral Fellow, UCL Cancer Institute
2018-2019: Research Fellow, Centre of Cardiovascular Science, University of Edinburgh
Other Appointments
2022-present: UK Committee on Research Integrity (UK CORI)
Awards and Prizes
2025: The Royal Society of Edinburgh Dame Anne McLaren Medal
Recent Publications
*Corresponding author
2026
Mruk O & Madsen RR*. PI3K inhibitor-free differentiation and maturation of human iPSC-derived arterialand venous-like endothelial cells. bioRxiv. 2026.
2025
Brunsdon H, Wang N, Raredon MSB, Madsen RR, Semple RK, Patton EE. Mosaic hotspot PIK3CA mutations cause non-cell-autonomous vascular overgrowth and pan-lineage dysregulation at disease onset.
bioRxiv. 2025.
Goetz A, Barrios J, Madsen RR, Dixit P. Non-equilibrium strategies for ligand specificity in signaling networks. eLife. 2025. 14:PR107524.
Mantoan Ritter L, Annear NMP, Baple EL, Ben-Chaabane LY, Bodi I, Brosson L, Cadwgan JE, Coslett B, Crosby AH, Davies DM, Daykin N, Dedeurwaerdere S, Dühring Fenger C, Dunlop EA, Elmslie FV, Girodengo M, Hambleton S, Jansen AC, Johnson SR, Kearley KC, Kingswood JC, Laaniste L, Lachlan K, Latchford A, Madsen R.R., Mansour S, Mihaylov SR, Muhammed L, Oliver C, Pepper T, Rawlins LE, Schim van der Loeff I, Siddiqui A, Takhar P, Tatton-Brown K, Tee AR, Tibarewal P, Tye C, Ultanir SK, Vanhaesebroeck B, Zare B, Pal DK, Bateman JM. mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR nodemTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node. Orphanet J Rare Dis. 2025;20(1):256.
2024
Erickson EC, You I, Perry G, Dugourd A, Donovan K, Ros S, Moss J, Ziegler R, Williamson S, Crafter C, Johannes J, Barry S, Fischer E, Gray N, Madsen RR*, Toker A*. Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation. Science Signaling. 2024;17(825):eadf2670.
Hillis AL, Martin TD, Manchester HE, Hogstrom JM, Zhang N, Lecky E, Kozlova N, Persky NS, Root DE, Brown M, Cichowski K, Elledge SJ, Muranen T, Fruman DA, Barry ST, Clohessy JG, Madsen RR, Toker A. Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancerCholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer. Cancer Research. 2024;84(19):3250-3266.
Madsen RR*, Le Marois A, Mruk O, Voliotis M, Yin S, Sufi J, Qin X, Zhao SJ, Gorczynska J, Morelli D, Davidson L, Sahai E, Korolchuk VI, Tape CJ, Vanhaesebroeck B. Oncogenic PIK3CA corrupts growth factor signaling specificityOncogenic PIK3CA corrupts growth factor signaling specificity. Molecular Systems Biology. 2024; 21:126-157.
Opzoomer J.W., O’Sullivan R., Sufi J., Madsen R.R., Qin X., Basiarz E., Tape C.J. SIGNAL-seq: Multimodal Single-cell Inter- and Intra-cellular Signalling Analysis. bioRxiv. 2024.
2023
Gong GQ, Allsop B, Masson GR, Roberton V, Bilanges B, Askwith T, Oxenford S, Madsen RR, Conduit SE, Fitzek M, Collier M, Chan E, Feierberg I, Madin A, Morelli D, Bhamra A, Surinova S, Pinotsis N, Lopez-Guadamillas E, Wilcox M, Whitehead MA, Davidson SM, Yellow DM, Perisic O, Hooper A, Patel C, Bunney TD, Katan D, Smith D, Phillips J, Williams RL, Angell R, Vanhaesebroeck B. A small-molecule PI3Kα activator for cardioprotection and neuroregenerationA small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Nature. 2023;618(7963):159-168.
Madsen RR*, Toker A*. PI3K signaling through a biochemical systems lens. Journal of Biological Chemistry. 2023; 299(10), 105224.
2022
Madsen RR, Semple RK. PIK3CA-related overgrowth: silver bullets from the cancer arsenal? Trends in Molecular Medicine 2022;28:255–257.
Vanhaesebroeck B, Burke JE, Madsen RR. Precision Targeting of Mutant PI3Kα in Cancer by Selective DegradationPrecision Targeting of Mutant PI3Kα in Cancer by Selective Degradation. Cancer Discovery 2022;12:20–22.
2021
Madsen RR*, Erickson EC, Rueda OM, Robin X, Caldas C, Toker A, Semple RK, Vanhaesebroeck B. Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.PLOS Genetics. 2021;17, e1009876.
Madsen RR*, Longden J, Knox RG, Macleod K, Xavier R, Völlmy F, Moniz L, Carragher N, Vanhaesebroeck B, Linding R, Semple RK. NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cellsNODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells. Disease Models & Mechanisms. 2021;14(3):dmm.048298.
Rabanal-Ruiz Y, Byron A, Wirth A, Madsen RR, Sedlackova L, Hewitt G, Nelson G, Stingele J, Wills JC, Zhang T, Zeug A, Fässler R, Vanhaesebroeck B, Maddocks ODK, Ponimaskin E, Carroll B, Korolchuk V. mTORC1 activity is supported by spatial association with focal adhesions. Journal of Cell Biology. 2021; 220(5).
2020
Madsen RR*. PI3K in stemness regulation: from development to cancer. Biochemical Society Transactions. 2020;48:301-315.
Madsen RR*. Vanhaesebroeck B.* Cracking the context-specific PI3K signaling code. Science Signaling 2020, Jan 7; 13, eaay2940.
2019
Harman JL, Dobnikar L, Chappell J, Stokell BG, Dalby A, Foote K, Finigan A, Freire-Pritchett P, Taylor AL, Worssam MD, Madsen RR, Loche E, Uryga A, Bennett MR, Jorgensen HF. Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling. Arterioscler Thromb Vasc Biol. 2019;39(11):2289-2302.
Madsen RR* and Semple RK*. Luminescent peptide tagging enables efficient screening for CRISPRmediated knock-in in human induced pluripotent stem cells. Wellcome Open Res 2019;4:37
Madsen RR, Knox RG, Pearce W, Lopez S, Mahler-Araujo B, McGranahan N, Vanhaesebroeck B, Semple RK. Genetic activation of PIK3CA in human pluripotent stem cells reveals allele dose-dependent developmental effects. PNAS 2019;116:8380-8389.
Vanhaesebroeck B., Bilanges B., Madsen R.R., Dale, K.L., Lau, E., Vladimirou, E. Perspective: Potential impact and therapeutic implications of oncogenic PI3K activation on chromosomal instabilityPerspective: Potential impact and therapeutic implications of oncogenic PI3K activation on chromosomal instability. Biomolecules. 2019;9(8). pii: E331.
2018
Madsen RR, Vanhaesebroeck, B, Semple, RK. Cancer-Associated PIK3CA Mutations in Overgrowth DisordersCancer-Associated PIK3CA Mutations in Overgrowth Disorders. Trends in Molecular Medicine. 2018;24(10):856–870.
2015
Tarry-Adkins JL, Fernandez-Twinn DS, Madsen RR, Chen JH, Carpenter A, Hargreaves IP, McConnell JM and Ozanne SE. Coenzyme Q10 Prevents Insulin Signaling Dysregulation and Inflammation Prior to Development of Insulin Resistance in Male Offspring of a Rat Model of Poor Maternal Nutrition and Accelerated Postnatal Growth. Endocrinology. 2015;156(10):3528–3537.
