An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma

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Abstract

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis, and regression. Propranolol, the mainstay treatment, inhibits IH vessel formation via a β-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial SRY box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells (HemSC) uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss and gain of function of SOX18 confirmed it is both necessary and sufficient for R(+) propranolol suppression of the MVP, including regulation of sterol regulatory element binding protein 2 (SREBP2) and the rate-limiting enzyme HMG-CoA reductase (HMGCR). AThe biological relevance of the endothelial SOX18-MVP axis in IH patient tissue was demonstrated by nuclear co-localization of SOX18 and SREBP2. Functional validation in a preclinical IH xenograft model revealed that statins – competitive inhibitors of HMGCR – efficiently suppress IH vessel formation. We propose an novel endothelial SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. The pleiotropic effects of R(+) propranolol and statins along the SOX18-MVP axis to disable an endothelial-specific program may have therapeutic implications for other vascular disease entities involving pathological vasculogenesis and angiogenesis.

Authors

Annegret Holm, Matthew S. Graus, Jill Wylie-Sears, Jerry Wei Heng Tan, Maya Alvarez-Harmon, Luke Borgelt, Sana Nasim, Long Chung, Ashish Jain, Mingwei Sun, Liang Sun, Pascal Brouillard, Ramrada Lekwuttikarn, Yanfei Qi, Joyce Teng, Miikka Vikkula, Harry Kozakewich, John B. Mulliken, Mathias Francois, Joyce Bischoff