High-dose oncogenic PIK3CA drives constitutive cellular stemness through self-sustained TGFβ pathway activation

Oncogenic mutations activate phosphoinositide 3-kinase-alpha (PI3Kα) and are among the commonest somatic mutations in cancer. We recently demonstrated that the “hotspot” variant exerts striking allele dose-dependent effects on stemness in human pluripotent stem cells (hPSCs), and found multiple oncogenic copies in a substantial proportion of human cancers. This suggested that the consequences of oncogenic PI3K signaling may differ according to the strength of genetic activation. Here, to identify the stemness-promoting mechanism, we profiled isogenic wild-type, and iPSCs by high-depth transcriptomics, proteomics and reverse-phase protein arrays (RPPA). We report that the phenotypic switch in homozygous hPSCs occurs downstream of signaling “rewiring” towards self-sustained TGFβ pathway activation and increased expression, which was no longer reversible by pharmacological PI3Kα inhibition. Gene expression analysis of -associated human breast cancers in The Cancer Genome Atlas revealed increased expression of according to tumor stage and allele dosage. Together with the emerging link between NODAL re-expression and cancer aggressiveness, our data suggest that TGFβ pathway inhibitors warrant investigation in breast tumors stratified by allele dosage.