UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

Madsen, RR; Knox, RG; Pearce, W; Lopez, S; Mahler-Araujo, B; McGranahan, N; Vanhaesebroeck, B; (2019) Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner. Proceedings of the National Academy of Sciences of The United States of America 10.1073/pnas.1821093116. (In press). Green open access

[img]
Preview
Text
Vanhaesebroeck_Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner_VoR.pdf - ["content_typename_Published version" not defined]

Download (2MB) | Preview

Abstract

The PIK3CA gene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known as PIK3CA-related overgrowth spectrum (PROS). To determine the consequences of genetic PIK3CA activation in a developmental context of relevance to both PROS and cancer, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous knockin of PIK3CA H1047R While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for PIK3CA H1047R caused widespread, cancer-like transcriptional remodeling, partial loss of epithelial morphology, up-regulation of stemness markers, and impaired differentiation to all three germ layers in vitro and in vivo. Genetic analysis of PIK3CA-associated cancers revealed that 64% had multiple oncogenic PIK3CA copies (39%) or additional PI3K signaling pathway-activating "hits" (25%). This contrasts with the prevailing view that PIK3CA mutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenic PIK3CA activation and provide insight into the specific role of this pathway in human pluripotent stem cells.

Type: Article
Title: Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1821093116
Publisher version: https://doi.org/10.1073/pnas.1821093116
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: PI3K, PROS, cancer, genetics, pluripotent stem cells
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/10071929
Downloads since deposit
32Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item