Oncogenic <i>PIK3CA</i> promotes cellular stemness in an allele dose-dependent manner

Abstract

The <i>PIK3CA</i> gene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known as <i>PIK3CA</i>-related overgrowth spectrum (PROS). To determine the consequences of genetic <i>PIK3CA</i> 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 <i>PIK3CA</i>^{<i>H1047R</i>} While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for <i>PIK3CA</i>^{<i>H1047R</i>} 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 <i>PIK3CA</i>-associated cancers revealed that 64% had multiple oncogenic <i>PIK3CA</i> copies (39%) or additional PI3K signaling pathway-activating "hits" (25%). This contrasts with the prevailing view that <i>PIK3CA</i> mutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenic <i>PIK3CA</i> activation and provide insight into the specific role of this pathway in human pluripotent stem cells.