Oncogenic PIK3CA mutations cause lineage-selective niche corruption

Lineage identity shapes outcomes of activating PIK3CA variants in iPSC-derived vascular development, with mutant venous endothelium selectively triggering an endothelial-to-mesenchymal-transition-like program despite similar PI3K/AKT activation.

• Why it matters: Context-dependent pathology in cancers and non-malignant overgrowth disorders is lineage-selective, but the mechanisms linking oncogenic signalling to specific tissue niches remain unclear.
• What they did: Using patient-derived and CRISPR-engineered iPSC models, the study combined time-resolved single-cell signalling and transcriptomics to compare arterial versus venous endothelial responses to weakly and strongly activating PIK3CA variants.
• The result: Mutant venous endothelium showed allele-dependent HGF hypersecretion that induced venous-selective niche remodelling and malformed venous organoid development, which mutant-selective PI3K inhibition prevented but did not reverse once established.