TY - JOUR
T1 - Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner
AU - Madsen, Ralitsa R.
AU - Knox, Rachel G.
AU - Pearce, Wayne
AU - Lopez, Saioa
AU - Mahler-Araujo, Betania
AU - McGranahan, Nicholas
AU - Vanhaesebroeck, Bart
AU - Semple, Robert K.
N1 - Funding Information:
We thank the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre Human Induced Pluripotent Stem Cells Core Facility for reprogramming patient-derived dermal fibroblasts. We thank Dr. Anne-Claire Guenantin and Dr. Mo Mandegar for technical advice on stem cell culture. R.R.M. and R.K.S. are supported by the Wellcome Trust (105371/Z/14/Z, 210752/Z/18/Z) and United Kingdom (UK) NIHR Cambridge Biomedical Research Centre, and R.R.M. by a Boak Student Award from Clare Hall. B.V. is supported by Cancer Research UK (C23338/A25722), PTEN Research, and the UK NIHR University College London Hospitals Biomedical Research Centre. Metabolic Research Laboratories Core facilities are supported by the Medical Research Council Metabolic Diseases Unit (MC_UU_12012/5) and a Wellcome Major Award (208363/Z/17/Z). The University College London Cancer Institute Pathology Core Facility is supported by Cancer Research UK (C416-A25145). N.M. is Sir Henry Dale Fellow funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z). N.M. receives funding from Cancer Research UK, and Rosetrees Trust. S.L. received funding from the Rosetrees Trust.
Funding Information:
ACKNOWLEDGMENTS. We thank the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre Human Induced Pluripotent Stem Cells Core Facility for reprogramming patient-derived dermal fibroblasts. We thank Dr. Anne-Claire Guenantin and Dr. Mo Mandegar for technical advice on stem cell culture. R.R.M. and R.K.S. are supported by the Wellcome Trust (105371/Z/14/Z, 210752/Z/18/Z) and United Kingdom (UK) NIHR Cambridge Biomedical Research Centre, and R.R.M. by a Boak Student Award from Clare Hall. B.V. is supported by Cancer Research UK (C23338/ A25722), PTEN Research, and the UK NIHR University College London Hospitals Biomedical Research Centre. Metabolic Research Laboratories Core facilities are supported by the Medical Research Council Metabolic Diseases Unit (MC_UU_12012/5) and a Wellcome Major Award (208363/Z/17/Z). The University College London Cancer Institute Pathology Core Facility is supported by Cancer Research UK (C416-A25145). N.M. is Sir Henry Dale Fellow funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z). N.M. receives funding from Cancer Research UK, and Rosetrees Trust. S.L. received funding from the Rosetrees Trust.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/4/23
Y1 - 2019/4/23
N2 - 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 PIK3CAH1047R. While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for PIK3CAH1047R 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.
AB - 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 PIK3CAH1047R. While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for PIK3CAH1047R 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.
KW - Cancer
KW - Genetics
KW - PI3K
KW - Pluripotent stem cells
KW - PROS
UR - http://www.scopus.com/inward/record.url?scp=85065176928&partnerID=8YFLogxK
U2 - 10.1073/pnas.1821093116
DO - 10.1073/pnas.1821093116
M3 - Article
C2 - 30948643
AN - SCOPUS:85065176928
SN - 0027-8424
VL - 116
SP - 8380
EP - 8389
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -
