A key lesson that my PhD with Robert Semple taught me is that reductionist thinking alone falls short of solving the puzzle of complex biological phenomena let alone complex diseases. The discovery that one extra copy of an oncogenic PIK3CA mutation can have profound phenotypic consequences beyond those we commonly associate with the PI3K pathway is just one example. It drew my attention to the growing field of systems biology and the notion that biological circuits follow specific design principles that lend themselves to engineering/mathematical abstractions. As I wrote in a recent newsletter for the PROS patient community, ‘repairing’ a PIK3CA-mutant cell is akin to repairing a broken radio – one first needs to understand the system and its information processing principles based on the wiring of its components.
This realisation also served as inspiration for my Sir Henry Wellcome Fellowship. Simply put, my aim is to understand how context shapes the output of oncogenic PIK3CA activation with respect to control of cellular plasticity. These concepts and the questions they give rise to are covered in detail in the following two reviews:
- Madsen, R.R. and Vanhaesebroeck, B. Cracking the context-specific PI3K signaling code. Science Signaling 2020, Jan 7; 13, eaay2940
- Madsen, R.R. PI3K in stemness regulation: from development to cancer. Biochemical Society Transactions 2020, 48, pp. 301-315.
Publication list: research articles
Madsen, R.R., Erickson, E.C., Rueda, O.M., Robin, X., Caldas, C., Toker, A., Semple, R.K., Vanhaesebroeck, B. 2021. 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. doi: 10.1371/journal.pgen.1009876. Associated press release: https://www.eurekalert.org/news-releases/933803
Madsen, R.R., Longden, J., Knox, R.G., Macleod, K., Xavier, R., Völlmy, F., Moniz, L., Carragher, N., Vanhaesebroeck, B., Linding, R., Semple, R.K. 2019. NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells. Disease Models & Mechanisms. 2021, 14(3), p. dmm.048298. doi: 10.1242/dmm.048298. Associated first person interview: https://journals.biologists.com/dmm/article/14/3/dmm048939/237830/First-person-Ralitsa-Madsen
Madsen, R.R., Knox, R.G., Pearce, W., Lopez, S., Mahler-Araujo, B., McGranahan, N., Vanhaesebroeck, B., Semple, R.K. Genetic activation of PIK3CA in human pluripotent stem cells reveals allele dose-dependent developmental effects. PNAS 2019. 116, pp. 8380-8389.
Rabanal-Ruiz, Y., Byron, A., Wirth, A., Madsen, R., Sedlackova, L., Hewitt, G., Nelson, G., Stingele, J., Wills, J.C., Zhang, T., Zeug, A., Fässler, R., Vanhaesebroeck, B., Maddocks, O.D.K., Ponimaskin , E., Carroll, B., Korolchuk, V. 2020. mTORC1 activity is supported by spatial association with focal adhesions. Journal of Cell Biology 2021, 220(5). doi: 10.1083/jcb.202004010.
Harman, J.L., Dobnikar, L., Chappell, J., Stokell, B.G., Dalby, A., Foote, K., Finigan, A., Freire-Pritchett, P., Taylor, A.L., Worssam, M.D., Madsen, R.R., Loche, E., Uryga, A., Bennett, M.R., Jorgensen, H.F. 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, Aug 22:ATVBAHA119312765.
Madsen, R.R. and Semple, R.K. Luminescent peptide tagging enables efficient screening for CRISPR-mediated knock-in in human induced pluripotent stem cells [version 3; peer review: 2 approved]. Wellcome Open Res 2019, 4:37
Tarry-Adkins, J.L., Fernandez-Twinn, D.S., Madsen, R.R., Chen, J.H., Carpenter, A., Hargreaves, I.P., McConnell, J.M. and Ozanne, S.E. 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), pp. 3528–3537.
Publication list: reviews
Madsen, R.R., Semple, R.K. PIK3CA-related overgrowth: silver bullets from the cancer arsenal? Trends in Molecular Medicine 2022; https://doi.org/10.1016/j.molmed.2022.02.009
Vanhaesebroeck, B., Burke, J.E., Madsen, R.R. Precision Targeting of Mutant PI3Kα in Cancer by Selective Degradation. Cancer Discov. 2022, 12, 20–22.
Madsen, R.R. PI3K in stemness regulation: from development to cancer. Biochemical Society Transactions 2020, 48, pp. 301-315.
Madsen, R.R. and Vanhaesebroeck, B. Cracking the context-specific PI3K signaling code. Science Signaling 2020, Jan 7; 13, eaay2940
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 instability. Biomolecules 2019, Aug 1;9(8). pii: E331.
Madsen, R.R., Vanhaesebroeck, B. and Semple, R. K. Cancer-Associated PIK3CA Mutations in Overgrowth Disorders. Trends in Molecular Medicine 2018, 24(10), pp. 856–870.
PIK3CA-related overgrowth spectrum (PROS)
Beyond direct patient engagement and laboratory research of relevance to activating PIK3CA mutations, I contribute to PROS research by serving on the Scientific Advisory Board of CLOVES Syndrome Community.
Worldwide PI3K Zoom Seminar series
Together with Dr Neil Vasan (Associate Professor, Columbia University), I have been organising a weekly online seminar series for the PI3K science community since May 2020 – initially as a consequence of COVID-19 lockdown, but now continuing regardless. Talks are at 11 AM -12 PM EST (4-5 PM UK time), on Zoom, every second Friday. If you would like to attend/present, please add your details here.
I am a weekly literature curator for Biomed News since August 2019, focusing specifically on PI3K signalling the development and cancer. All issues can be accessed here.