{"gene":"CDH11","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"CDH11 promoter drives high-level transcriptional activation of USP6 oncogene in primary aneurysmal bone cysts via chromosomal translocation, creating a CDH11-USP6 fusion gene; rearrangements were restricted to spindle cells and absent in multinucleated giant cells, inflammatory cells, endothelial cells, and osteoblasts.","method":"FISH/cytogenetics, molecular rearrangement analysis on primary tumor tissue","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular demonstration of fusion gene in 52 primary ABCs with cell-type specificity, single lab but large cohort with clear positive/negative controls","pmids":["15509545"],"is_preprint":false},{"year":2010,"finding":"Cdh11 loss-of-function in murine retinoblastoma promotes tumor cell survival by reducing cell death (5- to 10-fold decrease in apoptotic markers including activated caspase-3) without affecting proliferation; Cdh11 knockdown in vitro increases β-catenin expression, placing Cdh11 as a pro-apoptotic tumor suppressor upstream of β-catenin.","method":"Cdh11 knockout mouse crossed with TAg-RB tumor model; in vitro siRNA knockdown with caspase-3 and β-catenin immunostaining; in vivo tumor volume and cell death quantification","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo with defined phenotypic readout, corroborated by in vitro knockdown with multiple orthogonal markers, single lab but multiple methods","pmids":["20421947"],"is_preprint":false},{"year":2015,"finding":"miR-27b directly targets the CDH11 3'UTR to suppress CDH11 expression, and CDH11 mediates epithelial-mesenchymal transition (EMT) by regulating E-cadherin, vimentin, and N-cadherin expression in cervical cancer cells.","method":"miR-27b overexpression/inhibition, CDH11 cDNA rescue transfection, siRNA knockdown, proliferation and invasion assays, EMT marker immunoblotting","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct targeting validated by CDH11 rescue and knockdown experiments, single lab, multiple functional readouts","pmids":["26706910"],"is_preprint":false},{"year":2018,"finding":"FOXF1 transcription factor directly binds Cdh2 and Cdh11 promoters to differentially regulate their transcription; FOXF1 deletion promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11) in lung myofibroblasts, which is a critical step driving pro-fibrotic myofibroblast invasion and collagen secretion. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion.","method":"Fibroblast-specific FOXF1 knockout mice, chromatin immunoprecipitation (ChIP) on Cdh2/Cdh11 promoters, in vitro invasion assays with CDH11 inhibition and CDH2 re-expression rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ChIP evidence for FOXF1 binding CDH11 promoter, genetic KO mouse model, in vitro rescue experiments with multiple orthogonal approaches","pmids":["29642003"],"is_preprint":false},{"year":2018,"finding":"CDH11 promotes liver fibrosis by activating hepatic stellate cells (HSCs); CDH11 mediates TGFβ-induced HSC activation, and CDH11-deficient mouse HSCs show decreased activation in vitro and reduced fibrogenesis in vivo following CCl4-induced chronic liver injury.","method":"CDH11-deficient mouse model, CCl4-induced fibrosis in vivo, in vitro HSC activation assays, TGFβ stimulation experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse with defined in vivo phenotype and in vitro mechanistic follow-up, single lab, two orthogonal methods","pmids":["30509494"],"is_preprint":false},{"year":2019,"finding":"EPHB6 mutation induces paclitaxel resistance via interaction with EPHA2, which promotes JNK-mediated CDH11 expression; elevated CDH11 then mediates cell adhesion-mediated drug resistance (CAM-DR) through RhoA/FAK activation. Targeted inhibition of CDH11 reversed acquired paclitaxel resistance.","method":"EPHB6 mutation cell line models, kinase inhibitor experiments, CDH11 siRNA knockdown, RhoA/FAK signaling readouts, drug resistance assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established via pathway inhibitors and CDH11 knockdown rescue, single lab, multiple signaling readouts","pmids":["31160603"],"is_preprint":false},{"year":2019,"finding":"In metastatic breast cancer cells co-cultured with CDH11-rich cancer-associated fibroblasts, anti-CDH11 antibody suppresses CDH11, β-catenin, fibronectin, and vimentin expression, abrogating cancer stem cell-like traits and metastasis; ectopic miR-335 expression suppresses CDH11 and downstream β-catenin/vimentin, while CDH11 inhibition upregulates miR-335.","method":"Anti-CDH11 monoclonal antibody treatment, miR-335 mimic/inhibitor transfection, co-culture with CAFs, in vivo xenograft tumor models, protein expression analysis","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo evidence with antibody and miRNA modulation, single lab but multiple orthogonal readouts","pmids":["31248373"],"is_preprint":false},{"year":2019,"finding":"C12orf59 upregulates CDH11 expression via NF-κB signaling; in turn, CDH11 promotes NF-κB binding to the C12orf59 promoter, forming a positive feedback loop that sustains gastric cancer cell metastatic ability.","method":"Gain- and loss-of-function studies in vitro and in vivo, NF-κB pathway inhibition, promoter binding assays, invasion/metastasis assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional regulatory loop demonstrated with gain/loss of function and pathway inhibition, single lab","pmids":["30987656"],"is_preprint":false},{"year":2021,"finding":"Pathogenic CDH11 heterozygous missense variants clustered around EC2-EC3 and EC3-EC4 linker regions (predicted to affect Ca2+ binding required for cadherin stability) significantly reduced cell-substrate trans adhesion activity; one EC3-EC4 linker variant caused changes in cell morphology, focal adhesion, and migration, suggesting a dominant negative effect. CDH11 protein is strongly expressed in human facial mesenchyme.","method":"Cell-substrate trans adhesion functional assays, cell morphology and focal adhesion imaging, migration assays, immunohistochemistry of human facial mesenchyme, exome sequencing validation","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays on five disease variants, single lab, validated in 19 subjects from 9 families","pmids":["33811546"],"is_preprint":false},{"year":2021,"finding":"Exosomal miR-127-3p from bone marrow-derived mesenchymal stem cells inhibits CDH11 in chondrocytes, blocking Wnt/β-catenin pathway activation; overexpression of CDH11 reverses the protective exosome effects by reactivating Wnt/β-catenin signaling in IL-1β-injured chondrocytes.","method":"Exosome isolation and transfer, miR-127-3p inhibition, CDH11 overexpression rescue, Wnt/β-catenin pathway readouts, IL-1β chondrocyte injury model","journal":"Journal of pain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — miRNA-CDH11-pathway axis established with rescue experiments, single lab, multiple functional readouts","pmids":["33574696"],"is_preprint":false},{"year":2021,"finding":"CDH11 overexpression in tongue squamous cell carcinoma cells increases adhesion to human oral epithelial cells and decreases their ability to undergo transcellular migration through epithelial cells, acting as a tumor suppressor for invasion without affecting proliferation, apoptosis, stemness, or direct migration.","method":"CDH11 overexpression, adhesion assays with oral epithelial cells, transcellular migration assays, proliferation and apoptosis assays","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined adhesion and transcellular migration phenotype with CDH11 OE, single lab, multiple orthogonal assays","pmids":["34295163"],"is_preprint":false},{"year":2021,"finding":"Cdh11-null mice (but not Cdh9-null mice) display multiple autism-like behavioral alterations, supporting a functional role for CDH11 in the neural circuits underlying autism spectrum disorder behaviors.","method":"Cdh11 knockout mouse behavioral studies (autism-relevant behavioral battery), comparison with Cdh9 knockout mice","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined behavioral phenotype and specificity control (Cdh9 KO), single lab","pmids":["34523068"],"is_preprint":false},{"year":2022,"finding":"Extracellular vesicles (EVs) from RUNX2-high breast cancer cells deliver CDH11 protein to osteoblasts, mediating specific EV recognition and inducing an osteogenic premetastatic niche; CDH11 in EVs works together with ITGA5 to facilitate subsequent bone colonization of breast cancer cells.","method":"In vitro and in vivo EV transfer assays, CDH11/ITGA5 protein identification in EVs by proteomics, osteoblast education experiments, breast cancer bone metastasis mouse models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro mechanistic evidence for EV-CDH11 in osteoblast education and premetastatic niche formation, single lab","pmids":["35149589"],"is_preprint":false},{"year":2023,"finding":"miR-101-3p directly targets CDH11 (and SOX9); inhibition of miR-101-3p restores CDH11 and SOX9 expression and prevents osteogenic differentiation/calcification of human aortic valve interstitial cells under calcific conditions.","method":"miR-101-3p mimic/inhibitor in primary HAVICs, CDH11/SOX9 expression readouts, calcification assays under osteogenic conditioned medium","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct targeting validated in primary human cells with functional calcification readout, single lab","pmids":["36809926"],"is_preprint":false},{"year":2023,"finding":"FOXF1 overexpression inhibits TGF-β1-induced bronchial epithelial cell injury, fibrosis, and EMT by suppressing CDH11 expression and CDH11-mediated Wnt/β-catenin pathway activation; CDH11 overexpression reverses these protective FOXF1 effects.","method":"FOXF1 and CDH11 overexpression in TGF-β1-treated BEAS-2B cells, Wnt/β-catenin pathway protein readouts, fibrosis/EMT marker analysis, proliferation and apoptosis assays","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistatic relationship established by rescue experiment, single lab, multiple pathway readouts","pmids":["36798677"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 (an m6A reader) promotes CDH11 translation by reading m6A-enriched sites on CDH11 transcripts, as demonstrated by RIP-seq and MeRIP-seq; increased CDH11 expression downstream of YTHDF1 promotes breast cancer osteoblast adhesion and facilitates bone metastasis.","method":"RNA-seq, MeRIP-seq, RIP-seq, molecular biology (YTHDF1 knockdown/overexpression), AAV-mediated shYTHDF1 delivery in intratibial injection models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-dependent translational regulation of CDH11 by YTHDF1 established with RIP-seq and MeRIP-seq plus in vivo functional validation, single lab","pmids":["38871245"],"is_preprint":false},{"year":2024,"finding":"CDH11 inhibits branched-chain ketoacid dehydrogenase to activate the mTOR pathway by interfering with branched-chain amino acid (BCAA) metabolism; CDH11 inhibitors (celecoxib and derivatives) regulate BCAA metabolism, increase ROS production, and activate the cGAS-STING pathway, suppressing lung metastasis in vivo.","method":"Single-cell RNA sequencing, spatial transcriptomics, CDH11 inhibitor treatment, BCAA metabolism assays, ROS measurement, cGAS-STING pathway readouts, NOD-SCID mouse lung metastasis models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between CDH11 and BCAA/mTOR/cGAS-STING established with pharmacological inhibition in vitro and in vivo, single lab","pmids":["39739317"],"is_preprint":false},{"year":2025,"finding":"CDH11 knockdown in advanced bladder cancer cell lines suppresses mitochondrial metabolic activity (confirmed by Flux analyzer) and inhibits tumor growth in vivo, without affecting proliferation, invasion, or migration in vitro; a CDH11 inhibitor similarly decreases mitochondrial activity in vitro and suppresses tumor growth in vivo.","method":"shRNA-mediated CDH11 knockdown, RNA-seq, metabolic flux analysis, subcutaneous xenograft mouse model, CDH11 inhibitor treatment","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic mechanism established with flux analyzer and RNA-seq, corroborated in vivo, single lab","pmids":["41263259"],"is_preprint":false},{"year":2025,"finding":"CDH11 promotes airway neutrophilic inflammation in severe asthma via FGFR1 signaling; intratracheal instillation of recombinant CDH11 recruits neutrophils to the lungs, and this recruitment is blocked by FGFR1 inhibition. Pharmacological CDH11 antagonism (SD133) reduces airway neutrophil accumulation and IL-6/TNF-α production without affecting eosinophilic or type 2 inflammation.","method":"Murine severe asthma models (TDI and OVA/CFA), CDH11 antagonist SD133, recombinant CDH11 intratracheal instillation, FGFR1 inhibitor experiments, bronchoalveolar lavage cytology, cytokine measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-mediated mechanism (FGFR1) established by gain-of-function (recombinant CDH11) and inhibitor rescue, multiple in vivo models, single lab","pmids":["41329017"],"is_preprint":false},{"year":2025,"finding":"CDH11 knockdown in esophageal squamous cell carcinoma suppresses proliferation and invasion, while overexpression enhances them; CDH11 knockdown attenuates JAK-STAT3 and AKT signaling. Celecoxib and DMC directly bind CDH11 and inhibit ESCC growth in vitro and in vivo.","method":"CDH11 siRNA knockdown and overexpression, JAK-STAT3/AKT signaling readouts, direct drug-CDH11 binding assay, xenograft mouse model","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement via signaling readouts with KD and OE, direct compound binding demonstrated, single lab","pmids":["40460640"],"is_preprint":false},{"year":2025,"finding":"USP14 deubiquitinase stabilizes CDH11 protein through deubiquitination; USP14 knockdown decreases CDH11 protein levels, and CDH11 overexpression rescues USP14 knockdown effects in IL-1β-stimulated chondrocytes, identifying USP14 as the deubiquitinating writer that prevents CDH11 proteasomal degradation.","method":"USP14 knockdown, CDH11 overexpression rescue, ubiquitination/deubiquitination assays, cell viability/apoptosis/ferroptosis readouts in IL-1β chondrocyte model","journal":"Clinical rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination mechanism demonstrated with genetic rescue experiment, single lab, multiple orthogonal readouts","pmids":["41653235"],"is_preprint":false},{"year":2026,"finding":"CDH11 promotes EMT and gastric cancer progression by upregulating TGF-β1 and activating TGF-β signaling; activated TGF-β signaling in turn enhances CDH11 transcription via binding of downstream transcription factor Snail2 to the CDH11 promoter, forming a positive feedback loop regulating invasion and metastasis.","method":"CDH11 gain/loss-of-function in GC cells, TGF-β1 expression and signaling readouts, Snail2 promoter binding assays, in vitro migration/invasion assays, lung metastasis in vivo model","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcription factor-promoter binding established with functional in vivo and in vitro validation, single lab","pmids":["42127732"],"is_preprint":false},{"year":2026,"finding":"miR-205a directly binds the 3'UTR of CDH11 mRNA (confirmed by dual-luciferase assay) and inhibits chondrocyte differentiation by suppressing CDH11; CDH11 functions as a positive regulator of chondrocyte differentiation by promoting Wnt/β-catenin signaling. Silencing miR-205a or overexpressing CDH11 promotes chondrogenesis via Wnt/β-catenin and upregulates Runx2 and BMP2.","method":"Dual-luciferase reporter assay for miR-205a/CDH11 3'UTR binding, miR-205a overexpression/silencing, CDH11 overexpression, Wnt/β-catenin pathway agonist rescue, chondrogenic differentiation markers (Runx2, BMP2) in avian embryonic models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct 3'UTR binding validated by luciferase, pathway rescue experiment, single lab with multiple orthogonal methods","pmids":["42091868"],"is_preprint":false},{"year":2025,"finding":"CDH11 knockout in lung fibroblasts suppresses fibroblast activation metrics (spreading and type I collagen expression), reduces Piezo1 expression, and decreases IL-6 secretion; blocking IL-6 signaling decreases CDH11 but not Piezo1 expression, establishing CDH11 as downstream of IL-6 and upstream of Piezo1/IL-6 in a feedforward fibroblast activation loop.","method":"CDH11 knockout fibroblasts in HA hydrogel platform, Piezo1 inhibition experiments, IL-6 signaling blockade, fibroblast-M2 macrophage co-culture, type I collagen expression and cell spreading readouts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined mechanistic dissection of CDH11/Piezo1/IL-6 axis, single lab preprint","pmids":["bio_10.1101_2025.09.16.674909"],"is_preprint":true},{"year":2017,"finding":"Loss-of-function mutations in CDH11 (homozygous truncating/indel variants) cause Elsahy-Waters syndrome; patient fibroblasts show absent CDH11 protein expression, decreased cell proliferation rate, and delayed osteogenic differentiation potential compared to heterozygous parent and healthy donors.","method":"Exome sequencing and Sanger validation, immunostaining for CDH11 in patient-derived fibroblasts, cell proliferation assays, osteogenic differentiation assays","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells with protein absence confirmed and functional consequences measured, single study","pmids":["28988429"],"is_preprint":false},{"year":2025,"finding":"Transcription factors SP1 and GR bind to the CDH11 gene promoter core region (at -36/-27 bp and -20/-11 bp relative to TSS, respectively) to regulate CDH11 expression in bovine skeletal muscle, as identified by dual luciferase reporter assays with the core regulatory region mapped to -129/+55 bp.","method":"Dual luciferase reporter assays, promoter deletion constructs, transcription factor binding site analysis, tissue expression analysis","journal":"Animals","confidence":"Low","confidence_rationale":"Tier 3 / Weak — promoter-binding established by luciferase reporter in bovine model, single lab, regulatory mechanism not yet validated in human cells","pmids":["40362031"],"is_preprint":false}],"current_model":"CDH11 (Cadherin-11/OB-cadherin) is a Ca2+-dependent homophilic cell-cell adhesion molecule whose extracellular EC domains mediate trans-dimerization; it functions as a context-dependent regulator of cell adhesion, migration, and differentiation, acting as a tumor suppressor (promoting apoptosis via caspase-3 and suppressing β-catenin) in some cancers while promoting invasion, EMT, and fibrosis in others through activation of TGF-β, Wnt/β-catenin, NF-κB, RhoA/FAK, JAK-STAT3, FGFR1, and mTOR/cGAS-STING signaling pathways; its expression is regulated transcriptionally by FOXF1 (direct promoter binding), Snail2 (in a TGF-β feedback loop), SP1/GR, and post-translationally by USP14-mediated deubiquitination, and at the mRNA level by miR-27b, miR-127-3p, miR-101-3p, and miR-205a; YTHDF1 promotes its translation via m6A reading; in fibrosis, CDH11 is a key mediator of myofibroblast and hepatic stellate cell activation, and CDH11 knockout suppresses fibroblast activation by reducing Piezo1 expression and IL-6 secretion."},"narrative":{"mechanistic_narrative":"CDH11 (Cadherin-11/OB-cadherin) is a Ca2+-dependent cell adhesion molecule whose extracellular EC domains mediate trans-adhesion and whose dysregulation acts as a context-dependent driver of differentiation, fibrosis, and tumor behavior [PMID:33811546, PMID:28988429]. Loss-of-function truncating mutations cause Elsahy-Waters syndrome, with patient fibroblasts showing absent CDH11 protein, reduced proliferation, and delayed osteogenic differentiation [PMID:28988429], while heterozygous missense variants clustered at EC2-EC3/EC3-EC4 linkers impair Ca2+-dependent trans adhesion and perturb focal adhesion and migration, consistent with dominant-negative effects in facial mesenchyme [PMID:33811546]. In fibrosis, CDH11 is a central mediator of myofibroblast and hepatic stellate cell activation: FOXF1 directly binds the Cdh11 promoter and a FOXF1-controlled switch from CDH2 to CDH11 drives pro-fibrotic myofibroblast invasion and collagen secretion, and CDH11 transduces TGF-β-induced stellate cell activation in liver injury [PMID:29642003, PMID:30509494]. In cancer, CDH11 plays opposing roles depending on context — it acts as a pro-apoptotic tumor suppressor upstream of β-catenin in retinoblastoma and restrains transcellular invasion in tongue carcinoma [PMID:20421947, PMID:34295163], yet promotes EMT, invasion, and metastasis through TGF-β/Snail2, NF-κB, Wnt/β-catenin, RhoA/FAK, and JAK-STAT3/AKT signaling in cervical, gastric, and esophageal cancers [PMID:26706910, PMID:30987656, PMID:42127732, PMID:40460640, PMID:31160603]. CDH11 also reprograms metabolism, inhibiting branched-chain ketoacid dehydrogenase to activate mTOR and modulating mitochondrial activity to support tumor growth [PMID:39739317, PMID:41263259], and is delivered via extracellular vesicles together with ITGA5 to educate osteoblasts and establish a bone premetastatic niche [PMID:35149589, PMID:38871245]. CDH11 expression is controlled transcriptionally by FOXF1, Snail2, and SP1/GR [PMID:29642003, PMID:42127732, PMID:40362031], at the mRNA level by multiple microRNAs targeting its 3'UTR (miR-27b, miR-127-3p, miR-101-3p, miR-205a) [PMID:26706910, PMID:33574696, PMID:36809926, PMID:42091868], translationally by the m6A reader YTHDF1 [PMID:38871245], and at the protein level by USP14-mediated deubiquitination that prevents proteasomal degradation [PMID:41653235]. Cdh11-null mice additionally display autism-like behaviors, indicating a role in neural circuits [PMID:34523068].","teleology":[{"year":2004,"claim":"Established that the CDH11 promoter can be hijacked oncogenically, driving high-level transcription of the USP6 oncogene through a fusion-generating translocation.","evidence":"FISH/cytogenetics and rearrangement analysis on primary aneurysmal bone cysts","pmids":["15509545"],"confidence":"Medium","gaps":["Does not address normal CDH11 protein function","Cell-type specificity of the translocation not mechanistically explained"]},{"year":2010,"claim":"Demonstrated that CDH11 acts as a pro-apoptotic tumor suppressor in vivo, promoting tumor cell death upstream of β-catenin rather than affecting proliferation.","evidence":"Cdh11 knockout mouse crossed with retinoblastoma model plus in vitro siRNA knockdown with caspase-3 and β-catenin readouts","pmids":["20421947"],"confidence":"High","gaps":["Molecular link between CDH11 adhesion and caspase-3 activation unresolved","How CDH11 suppresses β-catenin not defined"]},{"year":2017,"claim":"Linked CDH11 loss-of-function directly to a Mendelian disease, showing absent protein and impaired osteogenic differentiation underlie Elsahy-Waters syndrome.","evidence":"Exome sequencing with patient-derived fibroblast protein, proliferation, and osteogenic differentiation assays","pmids":["28988429"],"confidence":"Medium","gaps":["Tissue-level mechanism of malformation phenotypes not dissected","Single study"]},{"year":2018,"claim":"Identified FOXF1 as a direct transcriptional regulator of CDH11 and revealed a CDH2-to-CDH11 cadherin switch as a driver of fibrotic myofibroblast invasion.","evidence":"Fibroblast-specific FOXF1 knockout mice, ChIP on Cdh2/Cdh11 promoters, in vitro invasion rescue assays","pmids":["29642003"],"confidence":"High","gaps":["How the cadherin switch mechanically promotes invasion unresolved","Downstream effectors of CDH11 in myofibroblasts not defined"]},{"year":2018,"claim":"Extended CDH11's pro-fibrotic role to liver, showing it transduces TGF-β-induced hepatic stellate cell activation in vivo.","evidence":"CDH11-deficient mice with CCl4-induced fibrosis and in vitro HSC activation/TGF-β assays","pmids":["30509494"],"confidence":"Medium","gaps":["Position of CDH11 relative to canonical TGF-β signaling not mapped","Direct partners in stellate cells unknown"]},{"year":2015,"claim":"Established post-transcriptional control of CDH11 by miR-27b and placed CDH11 as an EMT regulator in cervical cancer.","evidence":"miR-27b modulation, CDH11 cDNA rescue, siRNA knockdown with EMT marker immunoblotting and invasion assays","pmids":["26706910"],"confidence":"Medium","gaps":["Direct 3'UTR binding not validated by reporter in this study","Pro-EMT role conflicts with tumor-suppressor reports, context not reconciled"]},{"year":2019,"claim":"Placed CDH11 within drug-resistance and metastatic signaling networks, downstream of EPHA2/JNK driving RhoA/FAK-mediated adhesion-dependent resistance and within an NF-κB positive feedback loop sustaining metastasis.","evidence":"EPHB6 mutant cell models, kinase/pathway inhibitors, CDH11 knockdown, NF-κB inhibition and promoter binding assays","pmids":["31160603","30987656","31248373"],"confidence":"Medium","gaps":["Whether CDH11 acts through adhesion or independent signaling unclear","Receptors transducing CDH11 in these contexts not all defined"]},{"year":2021,"claim":"Resolved structural determinants of CDH11 adhesion, showing EC linker missense variants impair Ca2+-dependent trans adhesion and behave dominant-negatively in facial mesenchyme.","evidence":"Cell-substrate trans adhesion, morphology/focal adhesion imaging, migration assays, IHC, exome sequencing across families","pmids":["33811546"],"confidence":"Medium","gaps":["No high-resolution structure of the dimerization interface","Link between adhesion defect and craniofacial phenotype incomplete"]},{"year":2021,"claim":"Identified miRNA-CDH11-Wnt/β-catenin axes governing chondrocyte and valve cell differentiation/calcification, with CDH11 driving Wnt activation.","evidence":"Exosomal miR-127-3p transfer and miR-101-3p modulation in primary chondrocytes and aortic valve interstitial cells with CDH11 rescue and pathway readouts","pmids":["33574696","36809926"],"confidence":"Medium","gaps":["Direct CDH11-to-Wnt mechanistic connection not biochemically defined","Context-dependent directionality of CDH11 in differentiation unexplained"]},{"year":2021,"claim":"Demonstrated a context where CDH11 functions as an invasion suppressor by enhancing tumor-epithelial adhesion and blocking transcellular migration, and linked CDH11 to autism-relevant neural circuits.","evidence":"CDH11 overexpression with adhesion/transcellular migration assays in oral carcinoma; Cdh11 knockout behavioral battery with Cdh9 control","pmids":["34295163","34523068"],"confidence":"Medium","gaps":["Neural substrate of behavioral phenotype not identified","Molecular basis of adhesion-driven invasion suppression undefined"]},{"year":2022,"claim":"Revealed an extracellular-vesicle role for CDH11 protein in establishing an osteogenic premetastatic niche, acting with ITGA5 to enable bone colonization.","evidence":"EV transfer assays, CDH11/ITGA5 proteomics, osteoblast education, breast cancer bone metastasis mouse models","pmids":["35149589"],"confidence":"Medium","gaps":["Receptor on osteoblasts recognizing EV-CDH11 not identified","Mechanism of CDH11-ITGA5 cooperation unresolved"]},{"year":2024,"claim":"Uncovered metabolic functions of CDH11, linking it to BCAA metabolism/mTOR activation and identifying druggable nodes that engage ROS and cGAS-STING.","evidence":"Single-cell/spatial transcriptomics, CDH11 inhibitor treatment, BCAA/ROS/cGAS-STING readouts, lung metastasis models; YTHDF1 m6A regulation by RIP-seq/MeRIP-seq","pmids":["38871245","39739317"],"confidence":"Medium","gaps":["How a cadherin mechanistically inhibits branched-chain ketoacid dehydrogenase unclear","Whether metabolic effects require adhesion function not tested"]},{"year":2025,"claim":"Consolidated CDH11 as a pro-tumor signaling hub in squamous and bladder cancers (JAK-STAT3/AKT, mitochondrial activity) and as a druggable target bound directly by celecoxib/DMC.","evidence":"CDH11 knockdown/overexpression, signaling and metabolic flux readouts, direct compound-CDH11 binding assays, xenograft models","pmids":["40460640","41263259"],"confidence":"Medium","gaps":["Direct effectors coupling CDH11 to STAT3/AKT not identified","Reconciliation of pro- vs anti-tumor roles across tissues unresolved"]},{"year":2025,"claim":"Defined CDH11 receptor and feedforward mechanisms in inflammation and fibrosis, signaling through FGFR1 to recruit neutrophils and through a Piezo1/IL-6 loop in fibroblast activation.","evidence":"Recombinant CDH11 instillation with FGFR1 inhibition in asthma models; CDH11 knockout fibroblasts with Piezo1/IL-6 modulation (preprint)","pmids":["41329017","bio_10.1101_2025.09.16.674909"],"confidence":"Medium","gaps":["Whether CDH11 directly binds FGFR1 not shown","Piezo1/IL-6 axis preprint awaits peer review"]},{"year":2025,"claim":"Identified protein-level (USP14 deubiquitination) and additional transcriptional (SP1/GR) and miRNA (miR-205a) regulators completing the multilayer control of CDH11 abundance.","evidence":"USP14 knockdown with ubiquitination assays and CDH11 rescue; SP1/GR promoter luciferase mapping in bovine muscle; miR-205a 3'UTR luciferase with Wnt/β-catenin rescue","pmids":["41653235","40362031","42091868"],"confidence":"Medium","gaps":["SP1/GR regulation validated only in bovine model, not human","Coordination among the multiple regulatory layers not integrated"]},{"year":2026,"claim":"Established a CDH11-TGF-β1-Snail2 positive feedback loop driving EMT and gastric cancer metastasis.","evidence":"CDH11 gain/loss-of-function, TGF-β signaling readouts, Snail2 promoter binding, invasion and lung metastasis models","pmids":["42127732"],"confidence":"Medium","gaps":["How CDH11 upregulates TGF-β1 mechanistically unknown","Generality of the loop beyond gastric cancer untested"]},{"year":null,"claim":"It remains unresolved how a single adhesion molecule produces opposing tumor-suppressor versus pro-metastatic outcomes and how its adhesion function is mechanistically coupled to the diverse intracellular pathways (mTOR, FGFR1, JAK-STAT3, NF-κB) attributed to it.","evidence":"No timeline study reconciles context-dependent directionality or maps a unified signaling mechanism downstream of CDH11 trans-adhesion","pmids":[],"confidence":"Medium","gaps":["No structural model of CDH11 signaling complexes","Direct receptor partners for CDH11 ligand activity unconfirmed","Determinants of tissue-specific tumor-suppressor vs pro-tumor function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8,10,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[12,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[12,15]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,22,24]}],"complexes":[],"partners":["ITGA5","FGFR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55287","full_name":"Cadherin-11","aliases":["OSF-4","Osteoblast cadherin","OB-cadherin"],"length_aa":796,"mass_kda":88.0,"function":"Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. Required for proper focal adhesion assembly (PubMed:33811546). 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rearrangements were restricted to spindle cells and absent in multinucleated giant cells, inflammatory cells, endothelial cells, and osteoblasts.\",\n      \"method\": \"FISH/cytogenetics, molecular rearrangement analysis on primary tumor tissue\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular demonstration of fusion gene in 52 primary ABCs with cell-type specificity, single lab but large cohort with clear positive/negative controls\",\n      \"pmids\": [\"15509545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdh11 loss-of-function in murine retinoblastoma promotes tumor cell survival by reducing cell death (5- to 10-fold decrease in apoptotic markers including activated caspase-3) without affecting proliferation; Cdh11 knockdown in vitro increases β-catenin expression, placing Cdh11 as a pro-apoptotic tumor suppressor upstream of β-catenin.\",\n      \"method\": \"Cdh11 knockout mouse crossed with TAg-RB tumor model; in vitro siRNA knockdown with caspase-3 and β-catenin immunostaining; in vivo tumor volume and cell death quantification\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo with defined phenotypic readout, corroborated by in vitro knockdown with multiple orthogonal markers, single lab but multiple methods\",\n      \"pmids\": [\"20421947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-27b directly targets the CDH11 3'UTR to suppress CDH11 expression, and CDH11 mediates epithelial-mesenchymal transition (EMT) by regulating E-cadherin, vimentin, and N-cadherin expression in cervical cancer cells.\",\n      \"method\": \"miR-27b overexpression/inhibition, CDH11 cDNA rescue transfection, siRNA knockdown, proliferation and invasion assays, EMT marker immunoblotting\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct targeting validated by CDH11 rescue and knockdown experiments, single lab, multiple functional readouts\",\n      \"pmids\": [\"26706910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXF1 transcription factor directly binds Cdh2 and Cdh11 promoters to differentially regulate their transcription; FOXF1 deletion promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11) in lung myofibroblasts, which is a critical step driving pro-fibrotic myofibroblast invasion and collagen secretion. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion.\",\n      \"method\": \"Fibroblast-specific FOXF1 knockout mice, chromatin immunoprecipitation (ChIP) on Cdh2/Cdh11 promoters, in vitro invasion assays with CDH11 inhibition and CDH2 re-expression rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ChIP evidence for FOXF1 binding CDH11 promoter, genetic KO mouse model, in vitro rescue experiments with multiple orthogonal approaches\",\n      \"pmids\": [\"29642003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDH11 promotes liver fibrosis by activating hepatic stellate cells (HSCs); CDH11 mediates TGFβ-induced HSC activation, and CDH11-deficient mouse HSCs show decreased activation in vitro and reduced fibrogenesis in vivo following CCl4-induced chronic liver injury.\",\n      \"method\": \"CDH11-deficient mouse model, CCl4-induced fibrosis in vivo, in vitro HSC activation assays, TGFβ stimulation experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse with defined in vivo phenotype and in vitro mechanistic follow-up, single lab, two orthogonal methods\",\n      \"pmids\": [\"30509494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EPHB6 mutation induces paclitaxel resistance via interaction with EPHA2, which promotes JNK-mediated CDH11 expression; elevated CDH11 then mediates cell adhesion-mediated drug resistance (CAM-DR) through RhoA/FAK activation. Targeted inhibition of CDH11 reversed acquired paclitaxel resistance.\",\n      \"method\": \"EPHB6 mutation cell line models, kinase inhibitor experiments, CDH11 siRNA knockdown, RhoA/FAK signaling readouts, drug resistance assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established via pathway inhibitors and CDH11 knockdown rescue, single lab, multiple signaling readouts\",\n      \"pmids\": [\"31160603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In metastatic breast cancer cells co-cultured with CDH11-rich cancer-associated fibroblasts, anti-CDH11 antibody suppresses CDH11, β-catenin, fibronectin, and vimentin expression, abrogating cancer stem cell-like traits and metastasis; ectopic miR-335 expression suppresses CDH11 and downstream β-catenin/vimentin, while CDH11 inhibition upregulates miR-335.\",\n      \"method\": \"Anti-CDH11 monoclonal antibody treatment, miR-335 mimic/inhibitor transfection, co-culture with CAFs, in vivo xenograft tumor models, protein expression analysis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo evidence with antibody and miRNA modulation, single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"31248373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C12orf59 upregulates CDH11 expression via NF-κB signaling; in turn, CDH11 promotes NF-κB binding to the C12orf59 promoter, forming a positive feedback loop that sustains gastric cancer cell metastatic ability.\",\n      \"method\": \"Gain- and loss-of-function studies in vitro and in vivo, NF-κB pathway inhibition, promoter binding assays, invasion/metastasis assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional regulatory loop demonstrated with gain/loss of function and pathway inhibition, single lab\",\n      \"pmids\": [\"30987656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathogenic CDH11 heterozygous missense variants clustered around EC2-EC3 and EC3-EC4 linker regions (predicted to affect Ca2+ binding required for cadherin stability) significantly reduced cell-substrate trans adhesion activity; one EC3-EC4 linker variant caused changes in cell morphology, focal adhesion, and migration, suggesting a dominant negative effect. CDH11 protein is strongly expressed in human facial mesenchyme.\",\n      \"method\": \"Cell-substrate trans adhesion functional assays, cell morphology and focal adhesion imaging, migration assays, immunohistochemistry of human facial mesenchyme, exome sequencing validation\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays on five disease variants, single lab, validated in 19 subjects from 9 families\",\n      \"pmids\": [\"33811546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exosomal miR-127-3p from bone marrow-derived mesenchymal stem cells inhibits CDH11 in chondrocytes, blocking Wnt/β-catenin pathway activation; overexpression of CDH11 reverses the protective exosome effects by reactivating Wnt/β-catenin signaling in IL-1β-injured chondrocytes.\",\n      \"method\": \"Exosome isolation and transfer, miR-127-3p inhibition, CDH11 overexpression rescue, Wnt/β-catenin pathway readouts, IL-1β chondrocyte injury model\",\n      \"journal\": \"Journal of pain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — miRNA-CDH11-pathway axis established with rescue experiments, single lab, multiple functional readouts\",\n      \"pmids\": [\"33574696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDH11 overexpression in tongue squamous cell carcinoma cells increases adhesion to human oral epithelial cells and decreases their ability to undergo transcellular migration through epithelial cells, acting as a tumor suppressor for invasion without affecting proliferation, apoptosis, stemness, or direct migration.\",\n      \"method\": \"CDH11 overexpression, adhesion assays with oral epithelial cells, transcellular migration assays, proliferation and apoptosis assays\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined adhesion and transcellular migration phenotype with CDH11 OE, single lab, multiple orthogonal assays\",\n      \"pmids\": [\"34295163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cdh11-null mice (but not Cdh9-null mice) display multiple autism-like behavioral alterations, supporting a functional role for CDH11 in the neural circuits underlying autism spectrum disorder behaviors.\",\n      \"method\": \"Cdh11 knockout mouse behavioral studies (autism-relevant behavioral battery), comparison with Cdh9 knockout mice\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined behavioral phenotype and specificity control (Cdh9 KO), single lab\",\n      \"pmids\": [\"34523068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Extracellular vesicles (EVs) from RUNX2-high breast cancer cells deliver CDH11 protein to osteoblasts, mediating specific EV recognition and inducing an osteogenic premetastatic niche; CDH11 in EVs works together with ITGA5 to facilitate subsequent bone colonization of breast cancer cells.\",\n      \"method\": \"In vitro and in vivo EV transfer assays, CDH11/ITGA5 protein identification in EVs by proteomics, osteoblast education experiments, breast cancer bone metastasis mouse models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro mechanistic evidence for EV-CDH11 in osteoblast education and premetastatic niche formation, single lab\",\n      \"pmids\": [\"35149589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-101-3p directly targets CDH11 (and SOX9); inhibition of miR-101-3p restores CDH11 and SOX9 expression and prevents osteogenic differentiation/calcification of human aortic valve interstitial cells under calcific conditions.\",\n      \"method\": \"miR-101-3p mimic/inhibitor in primary HAVICs, CDH11/SOX9 expression readouts, calcification assays under osteogenic conditioned medium\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct targeting validated in primary human cells with functional calcification readout, single lab\",\n      \"pmids\": [\"36809926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXF1 overexpression inhibits TGF-β1-induced bronchial epithelial cell injury, fibrosis, and EMT by suppressing CDH11 expression and CDH11-mediated Wnt/β-catenin pathway activation; CDH11 overexpression reverses these protective FOXF1 effects.\",\n      \"method\": \"FOXF1 and CDH11 overexpression in TGF-β1-treated BEAS-2B cells, Wnt/β-catenin pathway protein readouts, fibrosis/EMT marker analysis, proliferation and apoptosis assays\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistatic relationship established by rescue experiment, single lab, multiple pathway readouts\",\n      \"pmids\": [\"36798677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 (an m6A reader) promotes CDH11 translation by reading m6A-enriched sites on CDH11 transcripts, as demonstrated by RIP-seq and MeRIP-seq; increased CDH11 expression downstream of YTHDF1 promotes breast cancer osteoblast adhesion and facilitates bone metastasis.\",\n      \"method\": \"RNA-seq, MeRIP-seq, RIP-seq, molecular biology (YTHDF1 knockdown/overexpression), AAV-mediated shYTHDF1 delivery in intratibial injection models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-dependent translational regulation of CDH11 by YTHDF1 established with RIP-seq and MeRIP-seq plus in vivo functional validation, single lab\",\n      \"pmids\": [\"38871245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDH11 inhibits branched-chain ketoacid dehydrogenase to activate the mTOR pathway by interfering with branched-chain amino acid (BCAA) metabolism; CDH11 inhibitors (celecoxib and derivatives) regulate BCAA metabolism, increase ROS production, and activate the cGAS-STING pathway, suppressing lung metastasis in vivo.\",\n      \"method\": \"Single-cell RNA sequencing, spatial transcriptomics, CDH11 inhibitor treatment, BCAA metabolism assays, ROS measurement, cGAS-STING pathway readouts, NOD-SCID mouse lung metastasis models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between CDH11 and BCAA/mTOR/cGAS-STING established with pharmacological inhibition in vitro and in vivo, single lab\",\n      \"pmids\": [\"39739317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDH11 knockdown in advanced bladder cancer cell lines suppresses mitochondrial metabolic activity (confirmed by Flux analyzer) and inhibits tumor growth in vivo, without affecting proliferation, invasion, or migration in vitro; a CDH11 inhibitor similarly decreases mitochondrial activity in vitro and suppresses tumor growth in vivo.\",\n      \"method\": \"shRNA-mediated CDH11 knockdown, RNA-seq, metabolic flux analysis, subcutaneous xenograft mouse model, CDH11 inhibitor treatment\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic mechanism established with flux analyzer and RNA-seq, corroborated in vivo, single lab\",\n      \"pmids\": [\"41263259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDH11 promotes airway neutrophilic inflammation in severe asthma via FGFR1 signaling; intratracheal instillation of recombinant CDH11 recruits neutrophils to the lungs, and this recruitment is blocked by FGFR1 inhibition. Pharmacological CDH11 antagonism (SD133) reduces airway neutrophil accumulation and IL-6/TNF-α production without affecting eosinophilic or type 2 inflammation.\",\n      \"method\": \"Murine severe asthma models (TDI and OVA/CFA), CDH11 antagonist SD133, recombinant CDH11 intratracheal instillation, FGFR1 inhibitor experiments, bronchoalveolar lavage cytology, cytokine measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-mediated mechanism (FGFR1) established by gain-of-function (recombinant CDH11) and inhibitor rescue, multiple in vivo models, single lab\",\n      \"pmids\": [\"41329017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDH11 knockdown in esophageal squamous cell carcinoma suppresses proliferation and invasion, while overexpression enhances them; CDH11 knockdown attenuates JAK-STAT3 and AKT signaling. Celecoxib and DMC directly bind CDH11 and inhibit ESCC growth in vitro and in vivo.\",\n      \"method\": \"CDH11 siRNA knockdown and overexpression, JAK-STAT3/AKT signaling readouts, direct drug-CDH11 binding assay, xenograft mouse model\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement via signaling readouts with KD and OE, direct compound binding demonstrated, single lab\",\n      \"pmids\": [\"40460640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP14 deubiquitinase stabilizes CDH11 protein through deubiquitination; USP14 knockdown decreases CDH11 protein levels, and CDH11 overexpression rescues USP14 knockdown effects in IL-1β-stimulated chondrocytes, identifying USP14 as the deubiquitinating writer that prevents CDH11 proteasomal degradation.\",\n      \"method\": \"USP14 knockdown, CDH11 overexpression rescue, ubiquitination/deubiquitination assays, cell viability/apoptosis/ferroptosis readouts in IL-1β chondrocyte model\",\n      \"journal\": \"Clinical rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination mechanism demonstrated with genetic rescue experiment, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"41653235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDH11 promotes EMT and gastric cancer progression by upregulating TGF-β1 and activating TGF-β signaling; activated TGF-β signaling in turn enhances CDH11 transcription via binding of downstream transcription factor Snail2 to the CDH11 promoter, forming a positive feedback loop regulating invasion and metastasis.\",\n      \"method\": \"CDH11 gain/loss-of-function in GC cells, TGF-β1 expression and signaling readouts, Snail2 promoter binding assays, in vitro migration/invasion assays, lung metastasis in vivo model\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcription factor-promoter binding established with functional in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"42127732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"miR-205a directly binds the 3'UTR of CDH11 mRNA (confirmed by dual-luciferase assay) and inhibits chondrocyte differentiation by suppressing CDH11; CDH11 functions as a positive regulator of chondrocyte differentiation by promoting Wnt/β-catenin signaling. Silencing miR-205a or overexpressing CDH11 promotes chondrogenesis via Wnt/β-catenin and upregulates Runx2 and BMP2.\",\n      \"method\": \"Dual-luciferase reporter assay for miR-205a/CDH11 3'UTR binding, miR-205a overexpression/silencing, CDH11 overexpression, Wnt/β-catenin pathway agonist rescue, chondrogenic differentiation markers (Runx2, BMP2) in avian embryonic models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct 3'UTR binding validated by luciferase, pathway rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"42091868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDH11 knockout in lung fibroblasts suppresses fibroblast activation metrics (spreading and type I collagen expression), reduces Piezo1 expression, and decreases IL-6 secretion; blocking IL-6 signaling decreases CDH11 but not Piezo1 expression, establishing CDH11 as downstream of IL-6 and upstream of Piezo1/IL-6 in a feedforward fibroblast activation loop.\",\n      \"method\": \"CDH11 knockout fibroblasts in HA hydrogel platform, Piezo1 inhibition experiments, IL-6 signaling blockade, fibroblast-M2 macrophage co-culture, type I collagen expression and cell spreading readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined mechanistic dissection of CDH11/Piezo1/IL-6 axis, single lab preprint\",\n      \"pmids\": [\"bio_10.1101_2025.09.16.674909\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss-of-function mutations in CDH11 (homozygous truncating/indel variants) cause Elsahy-Waters syndrome; patient fibroblasts show absent CDH11 protein expression, decreased cell proliferation rate, and delayed osteogenic differentiation potential compared to heterozygous parent and healthy donors.\",\n      \"method\": \"Exome sequencing and Sanger validation, immunostaining for CDH11 in patient-derived fibroblasts, cell proliferation assays, osteogenic differentiation assays\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells with protein absence confirmed and functional consequences measured, single study\",\n      \"pmids\": [\"28988429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Transcription factors SP1 and GR bind to the CDH11 gene promoter core region (at -36/-27 bp and -20/-11 bp relative to TSS, respectively) to regulate CDH11 expression in bovine skeletal muscle, as identified by dual luciferase reporter assays with the core regulatory region mapped to -129/+55 bp.\",\n      \"method\": \"Dual luciferase reporter assays, promoter deletion constructs, transcription factor binding site analysis, tissue expression analysis\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — promoter-binding established by luciferase reporter in bovine model, single lab, regulatory mechanism not yet validated in human cells\",\n      \"pmids\": [\"40362031\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH11 (Cadherin-11/OB-cadherin) is a Ca2+-dependent homophilic cell-cell adhesion molecule whose extracellular EC domains mediate trans-dimerization; it functions as a context-dependent regulator of cell adhesion, migration, and differentiation, acting as a tumor suppressor (promoting apoptosis via caspase-3 and suppressing β-catenin) in some cancers while promoting invasion, EMT, and fibrosis in others through activation of TGF-β, Wnt/β-catenin, NF-κB, RhoA/FAK, JAK-STAT3, FGFR1, and mTOR/cGAS-STING signaling pathways; its expression is regulated transcriptionally by FOXF1 (direct promoter binding), Snail2 (in a TGF-β feedback loop), SP1/GR, and post-translationally by USP14-mediated deubiquitination, and at the mRNA level by miR-27b, miR-127-3p, miR-101-3p, and miR-205a; YTHDF1 promotes its translation via m6A reading; in fibrosis, CDH11 is a key mediator of myofibroblast and hepatic stellate cell activation, and CDH11 knockout suppresses fibroblast activation by reducing Piezo1 expression and IL-6 secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDH11 (Cadherin-11/OB-cadherin) is a Ca2+-dependent cell adhesion molecule whose extracellular EC domains mediate trans-adhesion and whose dysregulation acts as a context-dependent driver of differentiation, fibrosis, and tumor behavior [#8, #24]. Loss-of-function truncating mutations cause Elsahy-Waters syndrome, with patient fibroblasts showing absent CDH11 protein, reduced proliferation, and delayed osteogenic differentiation [#24], while heterozygous missense variants clustered at EC2-EC3/EC3-EC4 linkers impair Ca2+-dependent trans adhesion and perturb focal adhesion and migration, consistent with dominant-negative effects in facial mesenchyme [#8]. In fibrosis, CDH11 is a central mediator of myofibroblast and hepatic stellate cell activation: FOXF1 directly binds the Cdh11 promoter and a FOXF1-controlled switch from CDH2 to CDH11 drives pro-fibrotic myofibroblast invasion and collagen secretion, and CDH11 transduces TGF-\\u03b2-induced stellate cell activation in liver injury [#3, #4]. In cancer, CDH11 plays opposing roles depending on context — it acts as a pro-apoptotic tumor suppressor upstream of \\u03b2-catenin in retinoblastoma and restrains transcellular invasion in tongue carcinoma [#1, #10], yet promotes EMT, invasion, and metastasis through TGF-\\u03b2/Snail2, NF-\\u03baB, Wnt/\\u03b2-catenin, RhoA/FAK, and JAK-STAT3/AKT signaling in cervical, gastric, and esophageal cancers [#2, #7, #21, #19, #5]. CDH11 also reprograms metabolism, inhibiting branched-chain ketoacid dehydrogenase to activate mTOR and modulating mitochondrial activity to support tumor growth [#16, #17], and is delivered via extracellular vesicles together with ITGA5 to educate osteoblasts and establish a bone premetastatic niche [#12, #15]. CDH11 expression is controlled transcriptionally by FOXF1, Snail2, and SP1/GR [#3, #21, #25], at the mRNA level by multiple microRNAs targeting its 3'UTR (miR-27b, miR-127-3p, miR-101-3p, miR-205a) [#2, #9, #13, #22], translationally by the m6A reader YTHDF1 [#15], and at the protein level by USP14-mediated deubiquitination that prevents proteasomal degradation [#20]. Cdh11-null mice additionally display autism-like behaviors, indicating a role in neural circuits [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that the CDH11 promoter can be hijacked oncogenically, driving high-level transcription of the USP6 oncogene through a fusion-generating translocation.\",\n      \"evidence\": \"FISH/cytogenetics and rearrangement analysis on primary aneurysmal bone cysts\",\n      \"pmids\": [\"15509545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address normal CDH11 protein function\", \"Cell-type specificity of the translocation not mechanistically explained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that CDH11 acts as a pro-apoptotic tumor suppressor in vivo, promoting tumor cell death upstream of \\u03b2-catenin rather than affecting proliferation.\",\n      \"evidence\": \"Cdh11 knockout mouse crossed with retinoblastoma model plus in vitro siRNA knockdown with caspase-3 and \\u03b2-catenin readouts\",\n      \"pmids\": [\"20421947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between CDH11 adhesion and caspase-3 activation unresolved\", \"How CDH11 suppresses \\u03b2-catenin not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked CDH11 loss-of-function directly to a Mendelian disease, showing absent protein and impaired osteogenic differentiation underlie Elsahy-Waters syndrome.\",\n      \"evidence\": \"Exome sequencing with patient-derived fibroblast protein, proliferation, and osteogenic differentiation assays\",\n      \"pmids\": [\"28988429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-level mechanism of malformation phenotypes not dissected\", \"Single study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FOXF1 as a direct transcriptional regulator of CDH11 and revealed a CDH2-to-CDH11 cadherin switch as a driver of fibrotic myofibroblast invasion.\",\n      \"evidence\": \"Fibroblast-specific FOXF1 knockout mice, ChIP on Cdh2/Cdh11 promoters, in vitro invasion rescue assays\",\n      \"pmids\": [\"29642003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the cadherin switch mechanically promotes invasion unresolved\", \"Downstream effectors of CDH11 in myofibroblasts not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended CDH11's pro-fibrotic role to liver, showing it transduces TGF-\\u03b2-induced hepatic stellate cell activation in vivo.\",\n      \"evidence\": \"CDH11-deficient mice with CCl4-induced fibrosis and in vitro HSC activation/TGF-\\u03b2 assays\",\n      \"pmids\": [\"30509494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Position of CDH11 relative to canonical TGF-\\u03b2 signaling not mapped\", \"Direct partners in stellate cells unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established post-transcriptional control of CDH11 by miR-27b and placed CDH11 as an EMT regulator in cervical cancer.\",\n      \"evidence\": \"miR-27b modulation, CDH11 cDNA rescue, siRNA knockdown with EMT marker immunoblotting and invasion assays\",\n      \"pmids\": [\"26706910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct 3'UTR binding not validated by reporter in this study\", \"Pro-EMT role conflicts with tumor-suppressor reports, context not reconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed CDH11 within drug-resistance and metastatic signaling networks, downstream of EPHA2/JNK driving RhoA/FAK-mediated adhesion-dependent resistance and within an NF-\\u03baB positive feedback loop sustaining metastasis.\",\n      \"evidence\": \"EPHB6 mutant cell models, kinase/pathway inhibitors, CDH11 knockdown, NF-\\u03baB inhibition and promoter binding assays\",\n      \"pmids\": [\"31160603\", \"30987656\", \"31248373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDH11 acts through adhesion or independent signaling unclear\", \"Receptors transducing CDH11 in these contexts not all defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved structural determinants of CDH11 adhesion, showing EC linker missense variants impair Ca2+-dependent trans adhesion and behave dominant-negatively in facial mesenchyme.\",\n      \"evidence\": \"Cell-substrate trans adhesion, morphology/focal adhesion imaging, migration assays, IHC, exome sequencing across families\",\n      \"pmids\": [\"33811546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the dimerization interface\", \"Link between adhesion defect and craniofacial phenotype incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified miRNA-CDH11-Wnt/\\u03b2-catenin axes governing chondrocyte and valve cell differentiation/calcification, with CDH11 driving Wnt activation.\",\n      \"evidence\": \"Exosomal miR-127-3p transfer and miR-101-3p modulation in primary chondrocytes and aortic valve interstitial cells with CDH11 rescue and pathway readouts\",\n      \"pmids\": [\"33574696\", \"36809926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CDH11-to-Wnt mechanistic connection not biochemically defined\", \"Context-dependent directionality of CDH11 in differentiation unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a context where CDH11 functions as an invasion suppressor by enhancing tumor-epithelial adhesion and blocking transcellular migration, and linked CDH11 to autism-relevant neural circuits.\",\n      \"evidence\": \"CDH11 overexpression with adhesion/transcellular migration assays in oral carcinoma; Cdh11 knockout behavioral battery with Cdh9 control\",\n      \"pmids\": [\"34295163\", \"34523068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neural substrate of behavioral phenotype not identified\", \"Molecular basis of adhesion-driven invasion suppression undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed an extracellular-vesicle role for CDH11 protein in establishing an osteogenic premetastatic niche, acting with ITGA5 to enable bone colonization.\",\n      \"evidence\": \"EV transfer assays, CDH11/ITGA5 proteomics, osteoblast education, breast cancer bone metastasis mouse models\",\n      \"pmids\": [\"35149589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on osteoblasts recognizing EV-CDH11 not identified\", \"Mechanism of CDH11-ITGA5 cooperation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered metabolic functions of CDH11, linking it to BCAA metabolism/mTOR activation and identifying druggable nodes that engage ROS and cGAS-STING.\",\n      \"evidence\": \"Single-cell/spatial transcriptomics, CDH11 inhibitor treatment, BCAA/ROS/cGAS-STING readouts, lung metastasis models; YTHDF1 m6A regulation by RIP-seq/MeRIP-seq\",\n      \"pmids\": [\"38871245\", \"39739317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a cadherin mechanistically inhibits branched-chain ketoacid dehydrogenase unclear\", \"Whether metabolic effects require adhesion function not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated CDH11 as a pro-tumor signaling hub in squamous and bladder cancers (JAK-STAT3/AKT, mitochondrial activity) and as a druggable target bound directly by celecoxib/DMC.\",\n      \"evidence\": \"CDH11 knockdown/overexpression, signaling and metabolic flux readouts, direct compound-CDH11 binding assays, xenograft models\",\n      \"pmids\": [\"40460640\", \"41263259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effectors coupling CDH11 to STAT3/AKT not identified\", \"Reconciliation of pro- vs anti-tumor roles across tissues unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined CDH11 receptor and feedforward mechanisms in inflammation and fibrosis, signaling through FGFR1 to recruit neutrophils and through a Piezo1/IL-6 loop in fibroblast activation.\",\n      \"evidence\": \"Recombinant CDH11 instillation with FGFR1 inhibition in asthma models; CDH11 knockout fibroblasts with Piezo1/IL-6 modulation (preprint)\",\n      \"pmids\": [\"41329017\", \"bio_10.1101_2025.09.16.674909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDH11 directly binds FGFR1 not shown\", \"Piezo1/IL-6 axis preprint awaits peer review\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified protein-level (USP14 deubiquitination) and additional transcriptional (SP1/GR) and miRNA (miR-205a) regulators completing the multilayer control of CDH11 abundance.\",\n      \"evidence\": \"USP14 knockdown with ubiquitination assays and CDH11 rescue; SP1/GR promoter luciferase mapping in bovine muscle; miR-205a 3'UTR luciferase with Wnt/\\u03b2-catenin rescue\",\n      \"pmids\": [\"41653235\", \"40362031\", \"42091868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SP1/GR regulation validated only in bovine model, not human\", \"Coordination among the multiple regulatory layers not integrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a CDH11-TGF-\\u03b21-Snail2 positive feedback loop driving EMT and gastric cancer metastasis.\",\n      \"evidence\": \"CDH11 gain/loss-of-function, TGF-\\u03b2 signaling readouts, Snail2 promoter binding, invasion and lung metastasis models\",\n      \"pmids\": [\"42127732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CDH11 upregulates TGF-\\u03b21 mechanistically unknown\", \"Generality of the loop beyond gastric cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single adhesion molecule produces opposing tumor-suppressor versus pro-metastatic outcomes and how its adhesion function is mechanistically coupled to the diverse intracellular pathways (mTOR, FGFR1, JAK-STAT3, NF-\\u03baB) attributed to it.\",\n      \"evidence\": \"No timeline study reconciles context-dependent directionality or maps a unified signaling mechanism downstream of CDH11 trans-adhesion\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CDH11 signaling complexes\", \"Direct receptor partners for CDH11 ligand activity unconfirmed\", \"Determinants of tissue-specific tumor-suppressor vs pro-tumor function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8, 10, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [12, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [12, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 22, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGA5\", \"FGFR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}