Inhibition of Wnt-hypersensitive intestinal tumor growth by anti-LRP6 VHH

Wnt/-catenin signaling performs central roles in adult tissue homeostasis and is initiated by Wnt-mediated activation of the Frizzled receptor and co-receptors LRP5 and LRP6. Recently, enhanced surface expression of Wnt receptors due to mutations in the E3 ubiquitin ligases RNF43 and ZNRF3 has emerged as a leading cause for cancer development. Thus, blocking receptor activity in these cancer subsets holds great promise for therapeutic applications. Here, we employed an in vitro library selection system (CIS-display technology) to identify single-domain antibody fragments (VHH) that specifically recognize and block Wnt3-mediated activation of LRP5 and LRP6, thereby strongly inhibiting Wnt/-catenin signaling in cells. Structural analysis revealed that the most potent VHHs interact with a central region in the third-propeller (P3) of LRP6, sterically interfering with Wnt3 binding. Importantly, we show that anti-LRP6P3 VHHs block the growth of Wnt-hypersensitive Rnf43-/-/Znrf3-/- intestinal tumor organoids, by exhaustion of the stem cell pool and driving their collective terminal differentiation. Thus, VHH-mediated targeting of LRP6 provides a promising strategy for treatment of Wnt-hypersensitive tumors. Emil Pot +31 6 28 36 79 41

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