OncogenicPIK3CApromotes cellular stemness in an allele dose-dependent manner

Abstract

ThePIK3CAgene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known asPIK3CA-related overgrowth spectrum (PROS). To determine the consequences of geneticPIK3CAactivation 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 ofPIK3CAH1047R. While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity forPIK3CAH1047Rcaused 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 ofPIK3CA-associated cancers revealed that 64% had multiple oncogenicPIK3CAcopies (39%) or additional PI3K signaling pathway-activating “hits” (25%). This contrasts with the prevailing view thatPIK3CAmutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenicPIK3CAactivation and provide insight into the specific role of this pathway in human pluripotent stem cells.