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Characterization of Wnt effector pathways is key for our understanding of these processes and for developing therapeutic strategies that aim to preserve tissue homeostasis. O-glycosylated cell surface proteins, such as \u03b1-dystroglycan (\u03b1-DG), mediate cellular adhesion to extracellular matrix components. We revealed a Wnt\/LARGE2\/\u03b1-DG signaling pathway which triggers this mode of colonic epithelial cell-to-matrix interaction in health and disease.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Next generation sequencing upon shRNA-mediated silencing of adenomatous polyposis coli (APC), and quantitative chromatin immunoprecipitation (qChIP) combined with CRISPR\/Cas9-mediated transcription factor binding site targeting characterized <jats:italic>LARGE2<\/jats:italic> as a Wnt target gene. Quantitative mass spectrometry analysis on size-fractionated, glycoprotein-enriched samples revealed functional O-glycosylation of \u03b1-DG by LARGE2 in CRC. The biology of Wnt\/LARGE2\/\u03b1-DG signaling was assessed by affinity-based glycoprotein enrichment, laminin overlay, CRC-to-endothelial cell adhesion, and transwell migration assays. Experiments on primary tissue, human colonic (tumor) organoids, and bioinformatic analysis of CRC cohort data confirmed the biological relevance of our findings.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Next generation sequencing identified the LARGE2 O-glycosyltransferase encoding gene as differentially expressed upon Wnt activation in CRC. Silencing of APC, conditional expression of oncogenic \u03b2-catenin and endogenous \u03b2-catenin-sequestration affected <jats:italic>LARGE2<\/jats:italic> expression. The first intron of <jats:italic>LARGE2<\/jats:italic> contained a CTTTGATC motif essential for Wnt-driven <jats:italic>LARGE2<\/jats:italic> expression, showed occupation by the Wnt transcription factor TCF7L2, and Wnt activation triggered LARGE2-dependent \u03b1-DG O-glycosylation and laminin-adhesion in CRC cells. Colonic crypts and organoids expressed <jats:italic>LARGE2<\/jats:italic> mainly in stem cell-enriched subpopulations. In human adenoma organoids, activity of the LARGE2\/\u03b1-DG axis was Wnt-dose dependent. <jats:italic>LARGE2<\/jats:italic> expression was elevated in CRC and correlated with the Wnt-driven molecular subtype and intestinal stem cell features. O-glycosylated \u03b1-DG represented a Wnt\/LARGE2-dependent feature in CRC cell lines and patient-derived tumor organoids. Modulation of LARGE2\/\u03b1-DG signaling affected CRC cell migration through laminin-coated membranes and adhesion to endothelial cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We conclude that the LARGE2 O-glycosyltransferase-encoding gene represents a direct target of canonical Wnt signaling and mediates functional O-glycosylation of \u03b1-dystroglycan (\u03b1-DG) in human colonic stem\/progenitor cells and Wnt-driven CRC. Our work implies that aberrant Wnt activation augments CRC cell-matrix adhesion by increasing LARGE\/\u03b1-DG-mediated laminin-adhesiveness.<\/jats:p>\n                \n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s12964-020-00561-6","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T10:03:01Z","timestamp":1593079381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Wnt-driven LARGE2 mediates laminin-adhesive O-glycosylation in human colonic epithelial cells and colorectal cancer"],"prefix":"10.1186","volume":"18","author":[{"given":"Vanessa","family":"Dietinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cira R.","family":"Garc\u00eda de Durango","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Wiechmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie L.","family":"Boos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlies","family":"Michl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Hermeking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Kuster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1651-2751","authenticated-orcid":false,"given":"Peter","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,25]]},"reference":[{"key":"561_CR1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/S0092-8674(02)01014-0","volume":"111","author":"M van de Wetering","year":"2002","unstructured":"van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, et al. 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FFPE tissue samples from the ApcMin mouse model were provided by the HH lab. Experimentation with these animals was approved by the Government of Upper Bavaria, Germany (AZ 55.2\u20131-54-2532-4-2014).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing financial interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"102"}}