Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Nicola Fenderico, Revina C. van Scherpenzeel, Michael Goldflam, Davide Proverbio, Ingrid Jordens, Tomica Kralj, Sarah Stryeck, Tarek Z. Bass, Guy Hermans, Christopher Ullman, Teodor Aastrup, Piet Gros, Madelon M. Maurice

ABSTRACT

Wnt-induced β-catenin-mediated transcription is a driving force for stem cell self-renewal during adult tissue homeostasis. Enhanced Wnt receptor expression due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 recently emerged as a leading cause for cancer development. Consequently, targeting canonical Wnt receptors such as LRP5/6 holds great promise for treatment of such cancer subsets. Here, we employ CIS display technology to identify single-domain antibody fragments (VHH) that bind the LRP6 P3E3P4E4 region with nanomolar affinity and strongly inhibit Wnt3/3a-induced β-catenin-mediated transcription in cells, while leaving Wnt1 responses unaffected. Structural analysis reveal that individual VHHs variably employ divergent antigen-binding regions to bind a similar surface in the third β-propeller of LRP5/6, sterically interfering with Wnt3/3a binding. Importantly, anti-LRP5/6 VHHs block the growth of Wnt-hypersensitive Rnf43/Znrf3-mutant intestinal organoids through stem cell exhaustion and collective terminal differentiation. Thus, VHH-mediated targeting of LRP5/6 provides a promising differentiation-inducing strategy for treatment of Wnt-hypersensitive tumors. More... »

PAGES

365

References to SciGraph publications

  • 2016-04. Wnt addiction of genetically defined cancers reversed by PORCN inhibition in ONCOGENE
  • 2012-04-29. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner in NATURE
  • 2001-05. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins in NATURE
  • 2016-01. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function in NATURE
  • 2014-01. Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny in NATURE METHODS
  • 2017-05. Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling in NATURE
  • 2007-10-25. Identification of stem cells in small intestine and colon by marker gene Lgr5 in NATURE
  • 2014-01. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2011-11. Crystal structures of the extracellular domain of LRP6 and its complex with DKK1 in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 1996-09. Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 1992-09. APC mutations occur early during colorectal tumorigenesis in NATURE
  • 2014-07-23. Comprehensive molecular characterization of gastric adenocarcinoma in NATURE
  • 2012-12. The complex world of WNT receptor signalling in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2006-07. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer in ONCOGENE
  • 2009-02. Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer in NATURE CHEMICAL BIOLOGY
  • 2009-05. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche in NATURE
  • 2012-08. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors in NATURE
  • 2008-06. Analyzing real-time PCR data by the comparative CT method in NATURE PROTOCOLS
  • 2017-03. Interplay between metabolic identities in the intestinal crypt supports stem cell function in NATURE
  • 2017-03. Wnt signaling in cancer in ONCOGENE
  • 2011-01. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts in NATURE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-08172-z

    DOI

    http://dx.doi.org/10.1038/s41467-018-08172-z

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111566905

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30664649


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