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

Madsen RR, Longden J, Knox RG, Robin X, Völlmy F, Macleod KG, Moniz L, Carragher NO, McGranahan N, Linding R, Vanhaesebroeck B, Semple RK.

Oncogenic PIK3CA mutations activate phosphoinositide 3-kinase-alpha (PI3Kα) and are among the commonest somatic mutations in cancer. We recently demonstrated that the “hotspot” variant PIK3CAH1047R exerts striking allele dose-dependent effects on stemness in human pluripotent stem cells (hPSCs), and found multiple oncogenic PIK3CA 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 PIK3CA activation. Here, to identify the stemness-promoting mechanism, we profiled isogenic wild-type, PIK3CAWT/H1047R and PIK3CAH1047R/H1047R iPSCs by high-depth transcriptomics, proteomics and reverse-phase protein arrays (RPPA). We report that the phenotypic switch in homozygous PIK3CAH1047R hPSCs occurs downstream of signaling “rewiring” towards self-sustained TGFβ pathway activation and increased NODAL expression, which was no longer reversible by pharmacological PI3Kα inhibition. Gene expression analysis of PIK3CA-associated human breast cancers in The Cancer Genome Atlas revealed increased expression of NODAL according to tumor stage and PIK3CAH1047R 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 PIK3CAH1047R allele dosage.

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