The regulatory logic underlying lineage-specific vulnerabilities to genetic PI3Kα activation.

A single mutation in a gene called *PIK3CA* can cause cells to grow out of control, leading to either cancer or a rare set of birth defects known as PROS (PIK3CA-related overgrowth spectrum), but the same mutation does not affect every cell type equally. Why this matters: In PROS, the mutation appears early in development but only causes overgrowth in certain tissues—for example, it might enlarge a limb but leave the brain untouched. Researchers do not understand why this cell-type restriction occurs. Without that knowledge, treatments remain blunt tools that cannot target only the affected cells. What the research does: The scientist will track how the E545K mutation changes developing cells over time, using single-cell RNA sequencing to see which genes turn on and CyTOF to measure signalling proteins. By comparing mutant and healthy cells, computational models will predict which molecular pathways drive the abnormal growth. If those pathways can be experimentally blocked to “rescue” mutant cells back to a normal state, the work would reveal new therapeutic targets for both PROS and PI3K-driven cancers. This is fundamental science—it asks how a single genetic change produces different outcomes in different tissues. A clearer understanding of that regulatory logic could eventually lead to tissue-specific treatments that spare healthy cells.