{"entity":{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","aka":[],"tldr":"Wnt/β-catenin is a developmental pathway hijacked by colorectal cancer. Normally a destruction complex keeps β-catenin low; losing APC lets it flood the nucleus and drive growth genes.","summary":"Without Wnt, β-catenin is phosphorylated by the destruction complex (APC, AXIN, GSK3β, CK1) and degraded. Wnt binding to Frizzled/LRP5/6 disables the complex; β-catenin accumulates, enters the nucleus, and with TCF/LEF drives MYC, cyclin D1, LGR5, AXIN2. APC loss initiates ~80% of colorectal cancers; CTNNB1 mutations occur in HCC, endometrial, and desmoid tumours; RNF43/RSPO alterations define a ligand-dependent subset. Wnt is also immunosuppressive (excludes dendritic cells). Drugs have been hard: porcupine inhibitors for RSPO/RNF43 tumours, tankyrase inhibitors, and nirogacestat (gamma-secretase, desmoid) are the closest.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Wnt_signaling_pathway","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Wnt_signaling_pathway"}],"tags":[],"related":[],"cancers":["colorectal","hcc","endometrial","gallbladder"],"sections":[],"technologies":["chemoprevention"],"targets":["gpc3"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"analogy":"β-catenin is a messenger constantly being shredded by a committee (APC and friends). A Wnt signal tells the committee to stand down. Colorectal cancer fires the committee (APC loss), so the messenger runs unchecked into the nucleus.","nodes":[{"id":"wnt","label":"Wnt ligand","x":20,"y":8},{"id":"fzd","label":"Frizzled / LRP5/6","x":20,"y":26},{"id":"rnf43","label":"RNF43 / RSPO","x":60,"y":12},{"id":"dc","label":"Destruction complex (APC, AXIN, GSK3β)","x":55,"y":45},{"id":"bcat","label":"β-catenin","x":55,"y":65},{"id":"tcf","label":"TCF/LEF","x":55,"y":82},{"id":"genes","label":"MYC, cyclin D1, LGR5","x":55,"y":97}],"edges":[{"from":"wnt","to":"fzd","type":"activates"},{"from":"rnf43","to":"fzd","type":"inhibits"},{"from":"fzd","to":"dc","type":"inhibits"},{"from":"dc","to":"bcat","type":"inhibits"},{"from":"bcat","to":"tcf","type":"activates"},{"from":"tcf","to":"genes","type":"activates"}],"interventions":["Porcupine inhibitors (RSPO-fusion / RNF43-mutant tumours, trials)","Gamma-secretase inhibitor nirogacestat in desmoid tumours (approved 2023)","Tankyrase inhibitors (preclinical/early)","Indirect: chemoprevention with aspirin/COX-2 in Lynch and FAP"]},"route":"/pathways/wnt/","neighbours":{"cancer":[{"id":"adrenocortical","kind":"cancer","name":"Adrenocortical carcinoma","route":"/cancers/adrenocortical/"},{"id":"ampullary","kind":"cancer","name":"Ampullary cancer (ampulla of Vater)","route":"/cancers/ampullary/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"craniopharyngioma","kind":"cancer","name":"Craniopharyngioma","route":"/cancers/craniopharyngioma/"},{"id":"desmoid-tumour","kind":"cancer","name":"Desmoid tumour","route":"/cancers/desmoid-tumour/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"fap-associated-colorectal-cancer","kind":"cancer","name":"Familial adenomatous polyposis-associated colorectal cancer","route":"/cancers/fap-associated-colorectal-cancer/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder 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cancer","route":"/cancers/prostate/"},{"id":"small-bowel","kind":"cancer","name":"Small intestine cancer (small bowel adenocarcinoma)","route":"/cancers/small-bowel/"},{"id":"solid-pseudopapillary-neoplasm","kind":"cancer","name":"Solid pseudopapillary neoplasm of the pancreas","route":"/cancers/solid-pseudopapillary-neoplasm/"},{"id":"wilms-tumor","kind":"cancer","name":"Wilms tumour (nephroblastoma)","route":"/cancers/wilms-tumor/"},{"id":"medulloblastoma-wnt","kind":"cancer","name":"WNT-activated medulloblastoma","route":"/cancers/medulloblastoma-wnt/"}],"technology":[{"id":"chemoprevention","kind":"technology","name":"Chemoprevention & risk-reducing surgery","route":"/technologies/chemoprevention/"}],"target":[{"id":"amer1","kind":"target","name":"AMER1","route":"/targets/amer1/"},{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"ctnnb1","kind":"target","name":"CTNNB1","route":"/targets/ctnnb1/"},{"id":"gpc3","kind":"target","name":"Glypican-3","route":"/targets/gpc3/"},{"id":"lgr5-gene","kind":"target","name":"LGR5","route":"/targets/lgr5-gene/"},{"id":"lrp5","kind":"target","name":"LRP5","route":"/targets/lrp5/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"rnf43","kind":"target","name":"RNF43","route":"/targets/rnf43/"},{"id":"rspo2","kind":"target","name":"RSPO2","route":"/targets/rspo2/"},{"id":"rspo3","kind":"target","name":"RSPO3","route":"/targets/rspo3/"},{"id":"tcf7l2","kind":"target","name":"TCF7L2","route":"/targets/tcf7l2/"}],"term":[{"id":"adenoma-carcinoma-sequence","kind":"term","name":"Adenoma-carcinoma sequence","route":"/terms/adenoma-carcinoma-sequence/"},{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","route":"/terms/cancer-stem-cell-theory/"},{"id":"colibactin","kind":"term","name":"Colibactin","route":"/terms/colibactin/"},{"id":"cms-subtypes","kind":"term","name":"Consensus molecular subtypes (CMS1-4)","route":"/terms/cms-subtypes/"},{"id":"evading-growth-suppressors","kind":"term","name":"Hallmark: evading growth suppressors","route":"/terms/evading-growth-suppressors/"},{"id":"lgr5","kind":"term","name":"LGR5","route":"/terms/lgr5/"},{"id":"rspo-fusion","kind":"term","name":"R-spondin fusion","route":"/terms/rspo-fusion/"},{"id":"signalling-pathway","kind":"term","name":"Signalling pathway","route":"/terms/signalling-pathway/"},{"id":"stem-cell","kind":"term","name":"Stem cell","route":"/terms/stem-cell/"}],"drug":[{"id":"nirogacestat","kind":"drug","name":"Nirogacestat","route":"/drugs/nirogacestat/"}],"trial":[{"id":"defi","kind":"trial","name":"DeFi","route":"/trials/defi/"}],"paper":[{"id":"paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018","kind":"paper","name":"Clinical sequencing defines the genomic landscape of metastatic colorectal cancer","route":"/key-papers/paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018/"},{"id":"paper-tcga-colorectal-comprehensive-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","route":"/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/"},{"id":"paper-wyatt-ctdna-tissue-concordance-mcrpc-jnci-2017","kind":"paper","name":"Concordance of circulating tumour DNA and matched metastatic tissue biopsy in prostate 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preservation","route":"/roadmaps/colorectal-roadmap/"}],"person":[{"id":"eric-fearon","kind":"person","name":"Eric R. Fearon","route":"/people/eric-fearon/"},{"id":"kenneth-kinzler","kind":"person","name":"Kenneth W. Kinzler","route":"/people/kenneth-kinzler/"}],"idea":[{"id":"idea-bio1-macrocycle-ppi-campaign","kind":"idea","name":"Macrocyclic peptides to cover protein surfaces that pills cannot","route":"/ideas/idea-bio1-macrocycle-ppi-campaign/"}],"pathway":[{"id":"breast-cancer-signalling","kind":"pathway","name":"Breast cancer (KEGG map)","route":"/pathways/breast-cancer-signalling/"},{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/"},{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"endometrial-cancer-signalling","kind":"pathway","name":"Endometrial cancer (KEGG map)","route":"/pathways/endometrial-cancer-signalling/"},{"id":"gastric-cancer-signalling","kind":"pathway","name":"Gastric cancer (KEGG map)","route":"/pathways/gastric-cancer-signalling/"},{"id":"hedgehog","kind":"pathway","name":"Hedgehog signalling","route":"/pathways/hedgehog/"},{"id":"hepatocellular-carcinoma-signalling","kind":"pathway","name":"Hepatocellular carcinoma (KEGG map)","route":"/pathways/hepatocellular-carcinoma-signalling/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"proteoglycans-in-cancer","kind":"pathway","name":"Proteoglycans in cancer","route":"/pathways/proteoglycans-in-cancer/"},{"id":"thyroid-cancer-signalling","kind":"pathway","name":"Thyroid cancer (KEGG map)","route":"/pathways/thyroid-cancer-signalling/"}]}}