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bioRxiv · 10.1101/495093

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

Madsen, R.·Knox, R.·Pearce, W.·Lopez, S.·Mahler-Araujo, B.·McGranahan, N.·Vanhaesebroeck, B.·Semple, R.
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Abstract

The PIK3CA gene, which encodes the p110 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 knock-in 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, upregulation 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 the first insight into the specific role of this pathway in human pluripotent stem cells.

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Madsen, R., Knox, R., Pearce, W., Lopez, S., Mahler-Araujo, B., McGranahan, N., Vanhaesebroeck, B., Semple, R.. 2018-12-13. Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner. https://doi.org/10.1101/495093

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