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bioRxiv · 10.1101/2024.01.29.577829

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

Holm, A.·Graus, M.·Wylie-Sears, J.·Borgelt, L.·Tan, J. W. H.·Nasim, S.·Chung, L.·Jain, A.·Sung, M.·Sun, L.·Brouillard, P.·Lekwuttikarn, R.·Kozakewich, H.·Qi, Y. J.·Teng, J.·Mulliken, J.·Vikkula, M.·Francois, M.·Bischoff, J.
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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 is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a {beta}-adrenergic receptor independent off-target 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. Our findings reveal novel pleiotropic effects of beta-blockers and statins acting on the SOX18-MVP axis to disable an endothelial specific program in IH, which may impact other scenarios involving pathological vasculogenesis and angiogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/577829v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@f02b2corg.highwire.dtl.DTLVardef@1a2790forg.highwire.dtl.DTLVardef@1ba0318org.highwire.dtl.DTLVardef@1213522_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Holm, A., Graus, M., Wylie-Sears, J., Borgelt, L., Tan, J. W. H., Nasim, S., Chung, L., Jain, A., Sung, M., Sun, L., Brouillard, P., Lekwuttikarn, R., Kozakewich, H., Qi, Y. J., Teng, J., Mulliken, J., Vikkula, M., Francois, M., Bischoff, J.. 2024-01-31. An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma. https://doi.org/10.1101/2024.01.29.577829

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