An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma [Day 6]

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 β-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. Hemangioma stem cells (HemSC) isolated from 6 different proliferating phase infantile hemangioma (2 to 6 months of age) were induced to undergo endothelial differentiation for 6 days. On Day 6 of differentiation, HemSC were treated with or without 20uM R (+) propranolol for 2 hours. Cells were lysed for total RNA isolation and library preparation using TruSeq stranded mRNA LT Sample Prep Kit and sequenced by Illumina paired end sequencing. Bulk-RNA-seq analysis was conducted with trimmomatic v0.39 to trim the low-quality next generation sequencing reads Subsequently, only the high-quality trimmed reads were aligned to the human reference genome (hg38) using STAR v2.7.2b . The reads counts were calculated by featureCounts software. Differentially expressed genes were identified by using the DESeq2 R package (adjusted p-value < 0.05).