PXD014719 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | High-dose oncogenic PIK3CA drives constitutive cellular stemness through increased NODAL/TGFb signaling |
Description | Oncogenic PIK3CA mutations activate phosphoinositide 3-kinase (PI3K) and are among the commonest somatic mutations in cancer and mosaic, developmental overgrowth disorders. We recently demonstrated that the ‘hotspot’ variant PIK3CAH1047R exerts striking allele dose-dependent effects on stemness in human induced pluripotent stem cells (iPSCs), and moreover demonstrated multiple oncogenic PIK3CA copies in a substantial subset of human cancers. To identify the molecular mechanism underpinning PIK3CAH1047R allele dose-dependent stemness, we profiled isogenic wild-type, PIK3CAWT/H1047R and PIK3CAH1047R/H1047R iPSCs by high-depth transcriptomics, proteomics and reverse-phase protein arrays (RPPA). PIK3CAH1047R/H1047R iPSCs exhibited altered expression of 5644 genes and 248 proteins, whereas heterozygous hPSCs showed 492 and 54 differentially-expressed genes and proteins, respectively, confirming a nearly deterministic phenotypic effect of homozygosity for PIK3CAH1047R. Pathway and network-based analyses predicted a strong association between self-sustained TGFb/NODAL signaling and the ‘locked’ stemness phenotype induced by homozygosity for PIK3CAH1047R. This stemness gene signature was maintained without exogenous NODAL in PIK3CAH1047R/H1047R iPSCs and was reversed by pharmacological inhibition of TGFb/NODAL signaling but not by PIK3CA-specific inhibition. Analysis of PIK3CA-associated human breast cancers revealed increased expression of the stemness markers NODAL and POU5F1 as a function of disease stage and PIK3CAH1047R allele dosage. Together with emerging realization of the link between NODAL re-expression and aggressive cancer behavior, our data suggest that TGFb/NODAL inhibitors warrant testing in advanced breast tumors with multiple oncogenic PIK3CA copies. |
HostingRepository | PRIDE |
AnnounceDate | 2021-03-03 |
AnnouncementXML | Submission_2021-03-02_22:42:55.788.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Franziska Voellmy |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue; acetylated residue; monohydroxylated residue |
Instrument | Orbitrap Fusion |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2019-07-23 06:45:22 | ID requested | |
⏵ 1 | 2021-03-02 22:42:56 | announced | |
Publication List
Madsen RR, Longden J, Knox RG, Robin X, V, ö, llmy F, Macleod KG, Moniz LS, Carragher NO, Linding R, Vanhaesebroeck B, Semple RK, signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells. Dis Model Mech, 14(3):(2021) [pubmed] |
Keyword List
submitter keyword: cancer, PIK3CA, TFGb, NODAL iPSC, proteomics, transcriptomics |
Contact List
Robert Semple |
contact affiliation | Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK |
contact email | rsemple@exseed.ed.ac.uk |
lab head | |
Franziska Voellmy |
contact affiliation | Utrecht University |
contact email | franziska.voellmy@gmail.com |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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[ - ]
- PRIDE
- PXD014719
- Label: PRIDE project
- Name: High-dose oncogenic PIK3CA drives constitutive cellular stemness through increased NODAL/TGFb signaling