Oncogenic PIK3CA corrupts growth factor signaling specificity
Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations of PI3K-specific information transfer for different growth factors. This features live-cell imaging of PI3K/AKT activity reporters and multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers over time. Using this framework, we found that the PIK3CA<sup>H1047R</sup> oncogene was not a simple, constitutive activator of the pathway as often presented. Dose-dependent expression of PIK3CA<sup>H1047R</sup> in human cervical cancer and induced pluripotent stem cells corrupted the fidelity of growth factor-induced information transfer, with preferential amplification of epidermal growth factor receptor (EGFR) signaling responses compared to insulin-like growth factor 1 (IGF1) and insulin receptor signaling. PIK3CA<sup>H1047R</sup> did not only shift these responses to a higher mean but also enhanced signaling heterogeneity. We conclude that oncogenic PIK3CA<sup>H1047R</sup> corrupts information transfer in a growth factor-dependent manner and suggest new opportunities for tuning of receptor-specific PI3K pathway outputs for therapeutic benefit.
Authors
- Jahangir Sufi (ORCID: https://orcid.org/0000-0002-4563-5531)
- L. S. P. Davidson (ORCID: https://orcid.org/0000-0002-2927-4377)
- Xiao Qin (ORCID: https://orcid.org/0000-0002-8738-4187)
- Salome Jingchen Zhao (ORCID: https://orcid.org/0009-0009-3715-0305)
- Alix Le Marois (ORCID: https://orcid.org/0000-0003-4464-4089)
- Bart Vanhaesebroeck (ORCID: https://orcid.org/0000-0002-7074-3673)
- Ralitsa Radostinova Madsen (ORCID: https://orcid.org/0000-0001-8844-5167)
- Christopher J. Tape (ORCID: https://orcid.org/0000-0003-4712-2737)
- Margaritis Voliotis (ORCID: https://orcid.org/0000-0001-6488-7198)
- Erik Sahai (ORCID: https://orcid.org/0000-0002-3932-5086)
- Viktor I. Korolchuk (ORCID: https://orcid.org/0000-0002-4071-592X)
- Oliwia N Mruk (ORCID: https://orcid.org/0009-0000-6516-3757)
- Shaozhen Yin
- Daniele Morelli (ORCID: https://orcid.org/0000-0002-3714-6658)
- Julia Gorczynska
Institutions
- University of Dundee (GB)
- University of Exeter (GB)
- The Francis Crick Institute (GB)
- Cancer Research UK (GB)
- London Cancer (GB)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- University College London (GB)
- Newcastle University (GB)
Publication Details
- Journal
- Molecular Systems Biology
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1038/s44320-024-00078-x
- Citations
- 10
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Eli Lilly and Company
- AstraZeneca
- Yale University
- University of Pittsburgh
- Wellcome Trust
- Francis Crick Institute
- Cancer Research UK
- University College London Hospitals NHS Foundation Trust
- Horizon 2020 Framework Programme
- Medical Research Council
- European Research Council
- UCLH Biomedical Research Centre