Development of a skin explant system for testing pharmacologic inhibitors of VGLL3-TEAD in murine lupus

Summary: Systemic lupus erythematosus is a strongly sex-biased disease that affects women at a 9:1 female-to-male ratio. We previously established that VGLL3, a transcription coregulator enriched in skin of women, drives expression of proinflammatory genes in keratinocytes. Murine models with epidermal overexpression of Vgll3 develop cutaneous and systemic lupus-like autoimmune disease that can be ameliorated with normalization of epidermal VGLL3 activity. VGLL proteins bind transcription factors including TEAD proteins. Here, we show that epidermal deletion of TEAD1 dramatically improves survival of mice with epidermal Vgll3-driven murine lupus, suggesting potential therapeutic benefit to VGLL3-TEAD targeting in lupus. However, VGLL3 competes for TEAD binding with the Hippo pathway effector YAP, whose activity is affected by cell density and matrix stiffness. This complicates study of pharmacologic inhibition in cell culture. We have thus developed a skin explant system to test candidate inhibitors of VGLL3-TEAD and YAP-TEAD in murine lupus-like disease. This system uses skin from mice with transgenic epidermal Vgll3 overexpression that is suppressible with doxycycline (K5-tTA;TRE3G-Vgll3-eGFP). We have identified conditions wherein doxycycline treatment reliably downregulates Vgll3 and linked reporter eGFP, as well as proinflammatory and profibrotic target genes that are robust across our systems such as Tnfsf18, Irf1, and Ctgf. Efforts to test predicted VGLL3-TEAD inhibitors and emerging YAP-TEAD inhibitors in clinical trials for oncologic applications are currently ongoing. The results of this work are anticipated to provide vital preclinical data supporting the further exploration of targeting VGLL3-TEAD inhibition in lupus patients with cutaneous involvement. Joanna E. Rew¹, Vincent van Drongelen¹, Emma Griffin¹, Li-Jyun Syu¹, Olesya Plazyo¹, Andrzej Dlugosz¹, Lam C. Tsoi¹, Johann E. Gudjonsson¹, Allison C. Billi¹ 1. University of Michigan, Ann Arbor, MI, United States. Adaptive and Auto-Immunity