PXD014719

PXD014719 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-23 06:45:22	ID requested
⏵ 1	2021-03-02 22:42:56	announced

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]

submitter keyword: cancer, PIK3CA, TFGb, NODAL iPSC, proteomics, transcriptomics

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

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PRIDE project URI

• PRIDE
  1. PXD014719
     1. Label: PRIDE project
     2. Name: High-dose oncogenic PIK3CA drives constitutive cellular stemness through increased NODAL/TGFb signaling