An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma [Day 4]

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis and regression. Propranolol is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a ß-adrenergic receptor independent effect of its R(+) enantiomer on the endothelial specific transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss of SOX18 function confirmed R(+) propranolol mode of action on the MVP. Functional validation in preclinical IH models revealed that statins - targeting the MVP - are potent inhibitors of hemangioma vessel formation. We propose a novel SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. Overall design: Hemangioma stem cells (HemSC) isolated from 3 different proliferating phase infantile hemangioma (3 to 6 months of age) were induced to undergo endothelial differentiation for 4 days. On Day 4 of differentiation, HemSC were treated with or without 20uM R(+) propranolol for 2 hours. Cells were lysed for RNA isolation. Bulk-RNA-seq was conducted with trimmomatic v0.39 to trim the low-quality next generation sequencing (NGS) reads (-threads 20 ILLUMINACLIP:TruSeq3-PE.fa:2:30:10 LEADING:3 TRAILING:3 SLIDINGWINDOW:4:15 MINLEN:36). Subsequently, only the high-quality trimmed reads were aligned to the human reference genome (hg38) using STAR v2.7.2b. The read counts were calculated by featureCounts software. Differentially expressed genes (DEGs) were identified by using the DESeq2 R package (adjusted p-value < 0.05).