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High-dose oncogenic PIK3CA drives constitutive cellular stemness through self-sustained TGFβ pathway activation

View ORCID ProfileRalitsa R. Madsen, View ORCID ProfileJames Longden, Rachel G. Knox, View ORCID ProfileXavier Robin, Franziska Völlmy, Kenneth G. Macleod, Larissa Moniz, View ORCID ProfileNeil O. Carragher, View ORCID ProfileNicholas McGranahan, View ORCID ProfileRune Linding, View ORCID ProfileBart Vanhaesebroeck, View ORCID ProfileRobert K. Semple
doi: https://doi.org/10.1101/753830
Ralitsa R. Madsen
Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKMetabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UKThe National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
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  • ORCID record for Ralitsa R. Madsen
  • For correspondence: rmadsen@ed.ac.uk rsemple@ed.ac.uk
James Longden
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkHumboldt-Universität zu Berlin, Berlin, Germany
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Rachel G. Knox
Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UKThe National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
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Xavier Robin
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Franziska Völlmy
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Kenneth G. Macleod
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, UK
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Larissa Moniz
University College London Cancer Institute, Paul O’Gorman Building, University College London, London, UK
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Neil O. Carragher
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, UK
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  • ORCID record for Neil O. Carragher
Nicholas McGranahan
University College London Cancer Institute, Paul O’Gorman Building, University College London, London, UK
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  • ORCID record for Nicholas McGranahan
Rune Linding
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkHumboldt-Universität zu Berlin, Berlin, Germany
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Bart Vanhaesebroeck
University College London Cancer Institute, Paul O’Gorman Building, University College London, London, UK
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Robert K. Semple
Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKMetabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UKThe National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
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  • For correspondence: rmadsen@ed.ac.uk rsemple@ed.ac.uk
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Abstract

Oncogenic PIK3CA mutations activate phosphoinositide 3-kinase-alpha (PI3Kα) and are among the commonest somatic mutations in cancer. We recently demonstrated that the “hotspot” variant PIK3CAH1047R exerts striking allele dose-dependent effects on stemness in human pluripotent stem cells (hPSCs), and found multiple oncogenic PIK3CA copies in a substantial proportion of human cancers. This suggested that the consequences of oncogenic PI3K signaling may differ according to the strength of genetic PIK3CA activation. Here, to identify the stemness-promoting mechanism, we profiled isogenic wild-type, PIK3CAWT/H1047R and PIK3CAH1047R/H1047R iPSCs by high-depth transcriptomics, proteomics and reverse-phase protein arrays (RPPA). We report that the phenotypic switch in homozygous PIK3CAH1047R hPSCs occurs downstream of signaling “rewiring” towards self-sustained TGFβ pathway activation and increased NODAL expression, which was no longer reversible by pharmacological PI3Kα inhibition. Gene expression analysis of PIK3CA-associated human breast cancers in The Cancer Genome Atlas revealed increased expression of NODAL according to tumor stage and PIK3CAH1047R allele dosage. Together with the emerging link between NODAL re-expression and cancer aggressiveness, our data suggest that TGFβ pathway inhibitors warrant investigation in breast tumors stratified by PIK3CAH1047R allele dosage.

One-sentence summary Biallelic genetic PI3Kα activation rewires signaling and induces constitutive stemness downstream from self-sustained TGFβ pathway activation.

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  • https://osf.io/muery/

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 01, 2019.
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High-dose oncogenic PIK3CA drives constitutive cellular stemness through self-sustained TGFβ pathway activation
Ralitsa R. Madsen, James Longden, Rachel G. Knox, Xavier Robin, Franziska Völlmy, Kenneth G. Macleod, Larissa Moniz, Neil O. Carragher, Nicholas McGranahan, Rune Linding, Bart Vanhaesebroeck, Robert K. Semple
bioRxiv 753830; doi: https://doi.org/10.1101/753830
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High-dose oncogenic PIK3CA drives constitutive cellular stemness through self-sustained TGFβ pathway activation
Ralitsa R. Madsen, James Longden, Rachel G. Knox, Xavier Robin, Franziska Völlmy, Kenneth G. Macleod, Larissa Moniz, Neil O. Carragher, Nicholas McGranahan, Rune Linding, Bart Vanhaesebroeck, Robert K. Semple
bioRxiv 753830; doi: https://doi.org/10.1101/753830

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