{"gene":"CCL18","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2011,"finding":"CCL18 released by breast tumor-associated macrophages promotes cancer cell invasiveness by triggering integrin clustering and enhancing adherence to extracellular matrix; PITPNM3 was identified as a functional receptor for CCL18 that mediates these effects and activates intracellular calcium signaling.","method":"Co-immunoprecipitation, calcium signaling assays, siRNA knockdown of PITPNM3, invasion/migration assays, xenograft mouse models","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional validation with receptor knockdown, calcium signaling assay, and in vivo xenograft rescue; replicated in multiple downstream studies","pmids":["21481794"],"is_preprint":false},{"year":2013,"finding":"Human chemokine receptor CCR8 is a functional receptor for CCL18; CCL18 induces chemotaxis and calcium flux via CCR8, binds CCR8 with high affinity, causes CCR8 internalization, and cross-desensitizes with CCL1 (the known CCR8 ligand) on Th2 cells.","method":"Chemotaxis assays with CCR8-transfected cells, calcium flux assays, competitive binding assays, receptor internalization assays, Ccr8-knockout mouse Th2 cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including competitive binding, calcium flux, chemotaxis, internalization, and genetic knockout confirmation","pmids":["23999500"],"is_preprint":false},{"year":2014,"finding":"Upon CCL18 binding to PITPNM3, Pyk2 translocates from the cytoplasm to the plasma membrane to form a stable complex with PITPNM3, subsequently activating Src kinase; Pyk2 and Src are essential for integrin alpha5/beta1 clustering-dependent adherence, migration, and invasion.","method":"Co-immunoprecipitation, immunofluorescence, Western blotting, Boyden chamber assay, adherence assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and functional assays in a single lab, moderate evidence","pmids":["24142406"],"is_preprint":false},{"year":2006,"finding":"CCL18 stimulates collagen production in pulmonary fibroblasts through a PKCalpha-mediated pathway: CCL18 triggers intracellular calcium increase, leading to PKCalpha phosphorylation and nuclear translocation, ERK2 phosphorylation, and collagen upregulation; this is independent of autocrine TGF-beta.","method":"Dominant-negative PKCalpha/ERK2 mutants, pharmacological inhibitor Gö6976, intracellular calcium chelation (BAPTA), collagen promoter reporter constructs, Western blotting","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 1-2 — dominant-negative mutagenesis and pharmacological inhibition with multiple readouts in a single lab","pmids":["16601239"],"is_preprint":false},{"year":2006,"finding":"CCL18-stimulated collagen upregulation in pulmonary fibroblasts requires Sp1 signaling (phosphorylation, DNA binding, reporter activity) and basal Smad3 activity, but is independent of autocrine TGF-beta.","method":"Dominant-negative Sp1 and Smad3 mutants, Sp1-dependent reporter assay, neutralizing anti-TGF-beta antibodies, ALK5 inhibitor, collagen mRNA/protein measurements","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 1-2 — dominant-negative mutagenesis and reporter assays with TGF-beta exclusion controls in a single lab","pmids":["16021625"],"is_preprint":false},{"year":2015,"finding":"CCL18 enhances HCC cell migration, invasion, and EMT via PITPNM3-dependent activation of NF-κB signaling (phosphorylation of IKK and IKBα, p65 nuclear translocation); these effects are abrogated by siRNA silencing of PITPNM3.","method":"siRNA knockdown of PITPNM3, Western blotting for p65 nuclear translocation and IKK/IKBα phosphorylation, migration/invasion assays","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA rescue experiment with mechanistic pathway readouts in a single lab","pmids":["26449829"],"is_preprint":false},{"year":2016,"finding":"CCL18 promotes NSCLC cell invasion and migration by binding to receptor Nir1 (PITPNM3), which activates RAC1-dependent cytoskeleton reorganization through ELMO1, and enhances cell adhesion via ELMO1-integrin β1 signaling.","method":"CCL18-Nir1 binding assays, RAC1 activation assays, siRNA knockdown of ELMO1, invasion/migration assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — receptor binding, downstream RAC1/ELMO1 signaling, and siRNA knockdown in a single lab","pmids":["26756176"],"is_preprint":false},{"year":2016,"finding":"CCL18 from ovarian cancer ascites promotes tumor cell migration via phosphorylation of proline-rich tyrosine kinase 2 (Pyk2); siRNA-mediated downregulation of Pyk2 attenuates ascites- and CCL18-induced cell migration.","method":"siRNA knockdown of Pyk2, ectopic Pyk2 expression, Boyden chamber migration assay, CCL18 blocking antibodies, Western blotting for phospho-Pyk2","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA and overexpression with blocking antibody in multiple OC cell lines","pmids":["27613122"],"is_preprint":false},{"year":2022,"finding":"CCL18 from TAMs activates NF-κB signaling via PITPNM3 in fibroblasts to enhance IL-6 and IL-8 production, converting normal breast-resident fibroblasts into a CD10+GPR77+ chemoresistance-inducing CAF phenotype.","method":"Co-culture systems, anti-CCL18 antibody blocking, Western blotting, siRNA/overexpression, in vivo CCL18 intratumoral injection xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic in vitro and in vivo validation with antibody rescue in a single lab","pmids":["36418470"],"is_preprint":false},{"year":2013,"finding":"CCL18 inhibits CCR1, CCR2, CCR4, and CCR5-mediated chemotaxis without binding to these receptors; instead, CCL18 selectively displaces heparin-bound chemokines from glycosaminoglycans (GAGs) on the endothelial surface, thereby functioning as a regulatory inhibitor of chemokine-mediated leukocyte recruitment.","method":"Schild plot analysis for competitive antagonism, binding assays to CCR-transfected cells, GAG displacement assays with heparin-bound chemokines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — functional antagonism with mechanistic GAG displacement assay, single lab","pmids":["23951310"],"is_preprint":false},{"year":2006,"finding":"Adenoviral overexpression of CCL18 in mouse lungs induces massive perivascular and peribronchial T lymphocyte infiltration and T lymphocyte-dependent collagen accumulation; T cell depletion abrogates CCL18-induced collagen deposition; CCL18 prestimulation of T cells upregulates TGF-beta1, which drives collagen production in T lymphocyte/fibroblast cocultures.","method":"Adenoviral gene delivery in vivo, antilymphocyte serum depletion, immunohistochemistry, flow cytometry, ELISA, T lymphocyte/fibroblast coculture","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic delivery with depletion rescue experiment, multiple readouts","pmids":["16868995"],"is_preprint":false},{"year":2010,"finding":"CCL18 attenuates CXCL12/CXCR4-mediated responses (calcium mobilization, chemotaxis, pseudo-emperipolesis, proliferation) in pre-B ALL cells by binding to GPR30; antibodies against GPR30 abolished CCL18 binding and its functional effects.","method":"Calcium flux assays, chemotaxis assays, GPR30-blocking antibodies, CCL18 binding to GPR30-expressing cells","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — receptor binding and functional inhibition assays in a single lab; GPR30 identification as CCL18 receptor requires further corroboration","pmids":["20568229"],"is_preprint":false},{"year":2003,"finding":"CCL18 production by immature dendritic cells is selectively down-regulated during maturation (by LPS, TNF, CD40L, pathogens), whereas IL-10 and vitamin D3 strongly promote CCL18 secretion; CCL18 was found to be chemotactic for immature dendritic cells.","method":"Cytokine stimulation of monocyte-derived DCs, ELISA for CCL18, chemotaxis assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 — functional chemotaxis and secretion assays, single lab but comprehensive panel of stimuli","pmids":["12646652"],"is_preprint":false},{"year":2019,"finding":"CCL18 promotes breast cancer metastasis via Annexin A2 as a downstream molecule of Nir1 (PITPNM3); CCL18 upregulates AnxA2 which promotes invasion and metastasis through the PI3K/Akt/GSK3β/Snail signaling pathway and F-actin polymerization via integrin β1.","method":"Western blot, siRNA knockdown of AnxA2, PI3K inhibitor LY294002, F-actin measurement, Matrigel invasion assay, spontaneous metastasis in SCID mice","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo validation with siRNA and pharmacological inhibition","pmids":["31894281"],"is_preprint":false},{"year":2015,"finding":"CCL18 reduces miR98 and miR27b expression via the N-Ras/ERK/PI3K/NFκB/Lin28b signaling pathway, forming a positive feedback loop that sustains CCL18 signaling and promotes EMT and metastasis of breast cancer cells.","method":"miRNA expression profiling, pathway inhibitor studies, overexpression/knockdown of miR98 and miR27b, invasion/migration assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissection with miRNA and signaling inhibitors, single lab","pmids":["26244871"],"is_preprint":false},{"year":2018,"finding":"CCL18 promotes bladder cancer cell invasion, migration, and EMT by binding to CCR8; blocking CCR8 with a small molecule inhibitor or shRNA knockdown reverses CCL18-induced decrease in E-cadherin and increase in MMP-2 and VEGF-C.","method":"CCR8 shRNA knockdown, CCR8 small molecule inhibitor, Western blotting, invasion/migration assays","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 — receptor knockdown and pharmacological inhibition with mechanistic readouts, single lab","pmids":["30592282"],"is_preprint":false},{"year":2022,"finding":"In glioma, CCR8 is identified as a functional receptor for CCL18; downstream signaling involves ACP5 (acid phosphatase 5), and CCL18 promotes glioma cell growth and invasion via the CCR8-ACP5 axis.","method":"Humanized brain slice model with iPSC-derived human microglia, CCR8 identification, in vivo GBM mouse model, functional invasion assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — novel ex vivo and in vivo model with receptor and downstream signaling identification","pmids":["35417708"],"is_preprint":false},{"year":2008,"finding":"Thrombin stimulates CCL18 release from mature dendritic cells (LPS-matured, PAR1/PAR3-expressing) via Rho-dependent signaling; CCL18 release requires ERK1/2 and Rho kinase activation.","method":"PAR-activating peptides, ERK1/2 and Rho kinase pharmacological inhibitors, ELISA for CCL18, actin polymerization assays, immunofluorescence","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological dissection of signaling pathway with multiple inhibitors in a single lab","pmids":["18606675"],"is_preprint":false},{"year":2018,"finding":"ACAP4 is acetylated by PCAF acetyltransferase at Lys311 in response to CCL18 stimulation; dynamic acetylation of ACAP4 is essential for CCL18-induced breast cancer cell migration and invasion by reducing ACAP4 lipid-binding activity to permit robust ARF6-ACAP4 plasma membrane cycling.","method":"Mass spectrometry, co-IP of ACAP4 with PCAF, acetylation-mimicking and non-acetylatable ACAP4 mutants, cell migration assays","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 1-2 — mass spectrometric mapping of acetylation site, mutagenesis, and functional assays in a single lab","pmids":["30395269"],"is_preprint":false},{"year":2020,"finding":"Ezrin is acetylated by PCAF acetyltransferase in breast cancer cells in response to CCL18 stimulation; acetylation at the mapped site reduces ezrin lipid-binding activity, prevents Thr567 phosphorylation, and drives ezrin unfolding, enabling dynamic plasma membrane-cytosol cycling essential for CCL18-induced cell migration and invasion.","method":"Mass spectrometry, co-IP of ezrin with PCAF, atomic force microscopy, phosphorylation/acetylation mutants, cell migration assays","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 1-2 — mass spectrometry plus AFM structural analysis plus functional mutagenesis, single lab","pmids":["31638145"],"is_preprint":false},{"year":2022,"finding":"CCL18 activates the ARF6/Src/PI3K/Akt signaling pathway; CCL18 increases ARF6 expression and p-AMAP1 via suppression of miR-760 in high metastatic breast cancer cells; exosomal miR-760 secreted by CCL18-stimulated high-metastatic cells is taken up by low-metastatic cells and promotes ARF6-mediated Src/PI3K/Akt signaling and EMT.","method":"ARF6 knockdown, miR-760 mimic/inhibitor, exosome uptake assays, Western blotting, in vivo tumor growth/metastasis models","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 — ARF6 knockdown plus exosome mechanistic experiments with in vivo validation, single lab","pmids":["35399607"],"is_preprint":false},{"year":1999,"finding":"The PARC/CCL18 gene was generated by fusion of two MIP-1alpha/LD78alpha-like genes on chromosome 17q11.2, explaining its high sequence similarity to MIP-1alpha but distinct chemotactic activity (toward lymphocytes rather than monocytes) and lack of shared receptor with MIP-1alpha.","method":"BAC clone genomic analysis, dot-plot sequence comparison, exon/intron structure analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 — genomic structural analysis establishing gene origin, single study","pmids":["10049593"],"is_preprint":false},{"year":2021,"finding":"M2-TAMs induce EMT of ovarian cancer cells by releasing CCL18; CCL18 induces M-CSF transcription in OvCa cells through ZEB1, and M-CSF drives M2 polarization of macrophages, establishing a CCL18-ZEB1-M-CSF positive feedback loop between OvCa cells and TAMs in spheroids.","method":"3D coculture, transwell coculture, RNA-sequencing, Western blot, qRT-PCR, ZEB1 knockdown, intraperitoneal mouse model","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — feedback loop dissected by ZEB1 knockdown in vitro and in vivo, single lab","pmids":["34969774"],"is_preprint":false},{"year":2024,"finding":"Lactate regulates CCL18 expression in macrophages via H3K18 lactylation; lactate-treated macrophages (acting through Gpr132) promote OV cell proliferation and migration, effects reversed by CCL18 silencing or anti-CCL18 antibody.","method":"ChIP-qPCR for H3K18 lactylation at CCL18 locus, luciferase reporter assay, Gpr132 siRNA knockdown, anti-CCL18 antibody, xenograft mouse model","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-qPCR epigenetic mechanism plus rescue experiments, single lab","pmids":["39010846"],"is_preprint":false}],"current_model":"CCL18, a primate-specific chemokine constitutively expressed in lung and plasma and abundantly produced by tumor-associated macrophages (M2-polarized), signals primarily through two identified receptors—PITPNM3 (Nir1) and CCR8—to activate downstream pathways including intracellular calcium signaling, Pyk2/Src kinase recruitment, NF-κB, PI3K/Akt, and ARF6/AMAP1, promoting integrin clustering, EMT, and cancer cell invasion/metastasis; it also stimulates collagen production in fibroblasts via PKCalpha/ERK2/Sp1 and basal Smad3 signaling, inhibits leukocyte recruitment by displacing chemokines from glycosaminoglycans, and has its own expression regulated epigenetically by H3K18 lactylation and transcriptionally by IL-4/IL-10/STAT6 signaling."},"narrative":{"teleology":[{"year":1999,"claim":"Determining CCL18's evolutionary origin resolved why it has lymphocyte-directed chemotactic activity distinct from its closest paralog MIP-1α despite high sequence identity.","evidence":"BAC clone genomic analysis showing CCL18 arose by fusion of two MIP-1α-like genes on 17q11.2","pmids":["10049593"],"confidence":"Medium","gaps":["No receptor identified at this stage","Functional divergence from MIP-1α not tested beyond chemotaxis"]},{"year":2003,"claim":"Establishing that CCL18 is constitutively produced by immature dendritic cells and suppressed upon maturation positioned it as a tolerogenic/anti-inflammatory chemokine, with IL-10 and vitamin D3 as key inducers.","evidence":"Cytokine stimulation panel of monocyte-derived DCs with ELISA and chemotaxis assays","pmids":["12646652"],"confidence":"Medium","gaps":["Receptor mediating DC chemotaxis unknown","In vivo relevance of DC-derived CCL18 not tested"]},{"year":2006,"claim":"Dissecting the pro-fibrotic signaling cascade showed that CCL18 stimulates collagen production in lung fibroblasts through calcium/PKCα/ERK2/Sp1 and basal Smad3, independent of autocrine TGF-β, and that in vivo CCL18 drives T cell-dependent pulmonary collagen deposition.","evidence":"Dominant-negative PKCα/ERK2/Sp1/Smad3 mutants, pharmacological inhibitors, adenoviral CCL18 delivery in mouse lungs with anti-lymphocyte serum depletion","pmids":["16601239","16021625","16868995"],"confidence":"Medium","gaps":["Fibroblast receptor for CCL18 not identified","Relationship between direct fibroblast stimulation and T cell-mediated collagen deposition unclear"]},{"year":2011,"claim":"Identification of PITPNM3 as a functional CCL18 receptor on breast cancer cells established the mechanistic basis for TAM-derived CCL18 driving integrin clustering, ECM adherence, and tumor invasiveness.","evidence":"Co-IP, calcium signaling, PITPNM3 siRNA knockdown, invasion assays, and xenograft mouse models","pmids":["21481794"],"confidence":"High","gaps":["PITPNM3 structure-function relationship with CCL18 unresolved","Whether PITPNM3 is the sole cancer-relevant receptor unclear"]},{"year":2013,"claim":"Discovery that CCR8 serves as a second high-affinity CCL18 receptor, and that CCL18 independently inhibits chemokine-mediated leukocyte recruitment by displacing GAG-bound chemokines, revealed dual receptor-dependent and receptor-independent immunomodulatory mechanisms.","evidence":"Competitive binding, calcium flux, chemotaxis on CCR8-transfected cells, Ccr8-KO Th2 cells; Schild plot analysis and GAG displacement assays","pmids":["23999500","23951310"],"confidence":"High","gaps":["Relative contribution of PITPNM3 vs CCR8 in different cell types not systematically compared","GAG displacement mechanism not validated in vivo"]},{"year":2014,"claim":"Elucidation of the Pyk2→Src kinase relay downstream of PITPNM3 established how CCL18 receptor engagement translates into integrin β1 clustering and cytoskeletal-dependent cell motility.","evidence":"Co-IP of Pyk2 with PITPNM3, immunofluorescence showing Pyk2 membrane translocation, Src activation by Western blot, invasion/adherence assays","pmids":["24142406"],"confidence":"Medium","gaps":["No structural data on PITPNM3-Pyk2 interface","Pyk2 phosphorylation site specificity not mapped"]},{"year":2015,"claim":"Demonstration that CCL18/PITPNM3 activates NF-κB (IKK/IκBα/p65) and N-Ras/ERK/PI3K/Lin28b pathways, and that CCL18 sustains its own signaling via miR-98/miR-27b suppression, broadened the downstream effector landscape to include EMT transcriptional programs.","evidence":"PITPNM3 siRNA in HCC cells; miRNA profiling, pathway inhibitors, overexpression/knockdown of miR-98 and miR-27b in breast cancer cells","pmids":["26449829","26244871"],"confidence":"Medium","gaps":["Positive feedback loop duration and in vivo relevance not established","NF-κB and miRNA arms not tested for cross-talk"]},{"year":2016,"claim":"Identification of ELMO1/RAC1 as effectors of CCL18/Nir1 signaling in NSCLC and confirmation of Pyk2 in ovarian cancer migration generalized the Pyk2-integrin and RAC1-cytoskeleton axes across tumor types.","evidence":"ELMO1 siRNA, RAC1 activation assays in NSCLC; Pyk2 siRNA/overexpression with CCL18 blocking antibody in ovarian cancer","pmids":["26756176","27613122"],"confidence":"Medium","gaps":["Whether ELMO1 and Pyk2 operate in the same or parallel branches not determined","Upstream adapter linking PITPNM3 to RAC1/ELMO1 unknown"]},{"year":2018,"claim":"Discovery that CCL18 triggers PCAF-mediated acetylation of ACAP4 and ezrin revealed a post-translational regulatory layer governing ARF6 membrane cycling and ezrin conformational dynamics essential for cell migration.","evidence":"Mass spectrometry of acetylation sites, PCAF co-IP, acetylation-mimicking/non-acetylatable mutants, AFM structural analysis, migration assays","pmids":["30395269","31638145"],"confidence":"Medium","gaps":["How CCL18 signal activates PCAF acetyltransferase not known","ACAP4/ezrin acetylation not validated in vivo"]},{"year":2022,"claim":"Convergent studies established CCL18 as a master organizer of the tumor microenvironment: it converts normal fibroblasts to chemoresistance-promoting CAFs via NF-κB/IL-6/IL-8, signals through CCR8-ACP5 in glioma, and propagates invasion via exosomal miR-760/ARF6.","evidence":"Co-culture with anti-CCL18 blocking, xenograft models; humanized brain slice and GBM mouse models; exosome uptake assays with ARF6 knockdown and in vivo metastasis","pmids":["36418470","35417708","35399607"],"confidence":"Medium","gaps":["Whether CAF conversion requires CCR8 or PITPNM3 on fibroblasts not tested","Exosomal miR-760 mechanism awaits independent replication"]},{"year":2024,"claim":"Identification of H3K18 lactylation at the CCL18 promoter in macrophages linked tumor-derived lactate metabolism to epigenetic control of CCL18 transcription, closing a regulatory loop between tumor glycolysis and TAM-mediated immune evasion.","evidence":"ChIP-qPCR for H3K18 lactylation, luciferase reporter, Gpr132 siRNA, anti-CCL18 antibody rescue, xenograft model","pmids":["39010846"],"confidence":"Medium","gaps":["Genome-wide specificity of lactylation-driven CCL18 regulation not assessed","Whether other epigenetic marks cooperate with H3K18la at the CCL18 locus unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CCL18 binding to PITPNM3 versus CCR8, the cell-type-specific partitioning of signaling between these receptors, and whether the GAG-displacement anti-inflammatory function operates in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of CCL18-receptor complexes","No systematic genetic model distinguishing PITPNM3 vs CCR8 contributions in vivo","GAG displacement function not validated in animal models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,9,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,9,10,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,5,6,13,14,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9,10,12,17]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,4,10]}],"complexes":[],"partners":["PITPNM3","CCR8","PYK2","ACAP4","ELMO1","PCAF"],"other_free_text":[]},"mechanistic_narrative":"CCL18 is a primate-specific CC-chemokine that functions as a pleiotropic mediator of immune regulation, tissue fibrosis, and cancer metastasis. It signals through two validated receptors—PITPNM3 (Nir1) and CCR8—to activate intracellular calcium flux, Pyk2/Src kinase cascades, NF-κB, PI3K/Akt, and ARF6 pathways, which collectively drive integrin clustering, cytoskeletal reorganization, epithelial-mesenchymal transition, and cancer cell invasion [PMID:21481794, PMID:23999500, PMID:24142406, PMID:26449829, PMID:35399607]. In fibroblasts, CCL18 stimulates collagen production through PKCα/ERK2/Sp1 signaling independently of autocrine TGF-β, and in vivo it promotes T lymphocyte-dependent pulmonary fibrosis [PMID:16601239, PMID:16021625, PMID:16868995]. CCL18 also attenuates leukocyte recruitment by displacing heparin-bound chemokines from glycosaminoglycans on endothelial surfaces, and its own expression in tumor-associated macrophages is regulated by IL-10, STAT6 signaling, and H3K18 lactylation at its promoter [PMID:23951310, PMID:12646652, PMID:39010846]."},"prefetch_data":{"uniprot":{"accession":"P55774","full_name":"C-C motif chemokine 18","aliases":["Alternative macrophage activation-associated CC chemokine 1","AMAC-1","CC chemokine PARC","Dendritic cell chemokine 1","DC-CK1","Macrophage inflammatory protein 4","MIP-4","Pulmonary and activation-regulated chemokine","Small-inducible cytokine A18"],"length_aa":89,"mass_kda":9.8,"function":"Chemotactic factor that attracts lymphocytes but not monocytes or granulocytes. May be involved in B-cell migration into B-cell follicles in lymph nodes. Attracts naive T-lymphocytes toward dendritic cells and activated macrophages in lymph nodes, has chemotactic activity for naive T-cells, CD4+ and CD8+ T-cells and thus may play a role in both humoral and cell-mediated immunity responses","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P55774/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCL18","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCL18","total_profiled":1310},"omim":[{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"},{"mim_id":"607003","title":"THYMIC STROMAL LYMPHOPOIETIN; TSLP","url":"https://www.omim.org/entry/607003"},{"mim_id":"603757","title":"CHEMOKINE, CC MOTIF, LIGAND 18; CCL18","url":"https://www.omim.org/entry/603757"},{"mim_id":"601834","title":"CHEMOKINE, CC MOTIF, RECEPTOR 8; CCR8","url":"https://www.omim.org/entry/601834"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lung","ntpm":46.6}],"url":"https://www.proteinatlas.org/search/CCL18"},"hgnc":{"alias_symbol":["DC-CK1","PARC","AMAC-1","DCCK1","MIP-4","CKb7"],"prev_symbol":["SCYA18"]},"alphafold":{"accession":"P55774","domains":[{"cath_id":"2.40.50.40","chopping":"2-88","consensus_level":"medium","plddt":86.9772,"start":2,"end":88}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55774","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55774-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55774-F1-predicted_aligned_error_v6.png","plddt_mean":86.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCL18","jax_strain_url":"https://www.jax.org/strain/search?query=CCL18"},"sequence":{"accession":"P55774","fasta_url":"https://rest.uniprot.org/uniprotkb/P55774.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55774/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55774"}},"corpus_meta":[{"pmid":"21481794","id":"PMC_21481794","title":"CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/21481794","citation_count":531,"is_preprint":false},{"pmid":"12969956","id":"PMC_12969956","title":"Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12969956","citation_count":252,"is_preprint":false},{"pmid":"15784687","id":"PMC_15784687","title":"Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes.","date":"2005","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/15784687","citation_count":216,"is_preprint":false},{"pmid":"15388468","id":"PMC_15388468","title":"Prevalence of mutations within the quinolone resistance-determining region of gyrA, gyrB, parC, and parE and association with antibiotic resistance in 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Korea)","url":"https://pubmed.ncbi.nlm.nih.gov/16273029","citation_count":22,"is_preprint":false},{"pmid":"23951310","id":"PMC_23951310","title":"CCL18 exhibits a regulatory role through inhibition of receptor and glycosaminoglycan binding.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23951310","citation_count":22,"is_preprint":false},{"pmid":"11310803","id":"PMC_11310803","title":"Molecular epidemiology and mutations at gyrA and parC genes of ciprofloxacin-resistant Escherichia coli isolates from a Taiwan medical center.","date":"2001","source":"Microbial drug resistance (Larchmont, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11310803","citation_count":22,"is_preprint":false},{"pmid":"31006523","id":"PMC_31006523","title":"The identification of CCL18 as biomarker of disease activity in localized scleroderma.","date":"2019","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/31006523","citation_count":22,"is_preprint":false},{"pmid":"31062206","id":"PMC_31062206","title":"Discovery of CCL18 antagonist blocking breast cancer metastasis.","date":"2019","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/31062206","citation_count":21,"is_preprint":false},{"pmid":"31638145","id":"PMC_31638145","title":"Acetylation of ezrin regulates membrane-cytoskeleton interaction underlying CCL18-elicited cell migration.","date":"2020","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31638145","citation_count":21,"is_preprint":false},{"pmid":"12473806","id":"PMC_12473806","title":"Mutation patterns in gyrA and parC genes of ciprofloxacin resistant isolates of Neisseria gonorrhoeae from India.","date":"2002","source":"Sexually transmitted infections","url":"https://pubmed.ncbi.nlm.nih.gov/12473806","citation_count":21,"is_preprint":false},{"pmid":"28222799","id":"PMC_28222799","title":"Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study.","date":"2017","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28222799","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51611,"output_tokens":5562,"usd":0.119132},"stage2":{"model":"claude-opus-4-6","input_tokens":9160,"output_tokens":3067,"usd":0.183713},"total_usd":0.302845,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"CCL18 released by breast tumor-associated macrophages promotes cancer cell invasiveness by triggering integrin clustering and enhancing adherence to extracellular matrix; PITPNM3 was identified as a functional receptor for CCL18 that mediates these effects and activates intracellular calcium signaling.\",\n      \"method\": \"Co-immunoprecipitation, calcium signaling assays, siRNA knockdown of PITPNM3, invasion/migration assays, xenograft mouse models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional validation with receptor knockdown, calcium signaling assay, and in vivo xenograft rescue; replicated in multiple downstream studies\",\n      \"pmids\": [\"21481794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human chemokine receptor CCR8 is a functional receptor for CCL18; CCL18 induces chemotaxis and calcium flux via CCR8, binds CCR8 with high affinity, causes CCR8 internalization, and cross-desensitizes with CCL1 (the known CCR8 ligand) on Th2 cells.\",\n      \"method\": \"Chemotaxis assays with CCR8-transfected cells, calcium flux assays, competitive binding assays, receptor internalization assays, Ccr8-knockout mouse Th2 cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including competitive binding, calcium flux, chemotaxis, internalization, and genetic knockout confirmation\",\n      \"pmids\": [\"23999500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Upon CCL18 binding to PITPNM3, Pyk2 translocates from the cytoplasm to the plasma membrane to form a stable complex with PITPNM3, subsequently activating Src kinase; Pyk2 and Src are essential for integrin alpha5/beta1 clustering-dependent adherence, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blotting, Boyden chamber assay, adherence assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and functional assays in a single lab, moderate evidence\",\n      \"pmids\": [\"24142406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CCL18 stimulates collagen production in pulmonary fibroblasts through a PKCalpha-mediated pathway: CCL18 triggers intracellular calcium increase, leading to PKCalpha phosphorylation and nuclear translocation, ERK2 phosphorylation, and collagen upregulation; this is independent of autocrine TGF-beta.\",\n      \"method\": \"Dominant-negative PKCalpha/ERK2 mutants, pharmacological inhibitor Gö6976, intracellular calcium chelation (BAPTA), collagen promoter reporter constructs, Western blotting\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — dominant-negative mutagenesis and pharmacological inhibition with multiple readouts in a single lab\",\n      \"pmids\": [\"16601239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CCL18-stimulated collagen upregulation in pulmonary fibroblasts requires Sp1 signaling (phosphorylation, DNA binding, reporter activity) and basal Smad3 activity, but is independent of autocrine TGF-beta.\",\n      \"method\": \"Dominant-negative Sp1 and Smad3 mutants, Sp1-dependent reporter assay, neutralizing anti-TGF-beta antibodies, ALK5 inhibitor, collagen mRNA/protein measurements\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — dominant-negative mutagenesis and reporter assays with TGF-beta exclusion controls in a single lab\",\n      \"pmids\": [\"16021625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCL18 enhances HCC cell migration, invasion, and EMT via PITPNM3-dependent activation of NF-κB signaling (phosphorylation of IKK and IKBα, p65 nuclear translocation); these effects are abrogated by siRNA silencing of PITPNM3.\",\n      \"method\": \"siRNA knockdown of PITPNM3, Western blotting for p65 nuclear translocation and IKK/IKBα phosphorylation, migration/invasion assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA rescue experiment with mechanistic pathway readouts in a single lab\",\n      \"pmids\": [\"26449829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCL18 promotes NSCLC cell invasion and migration by binding to receptor Nir1 (PITPNM3), which activates RAC1-dependent cytoskeleton reorganization through ELMO1, and enhances cell adhesion via ELMO1-integrin β1 signaling.\",\n      \"method\": \"CCL18-Nir1 binding assays, RAC1 activation assays, siRNA knockdown of ELMO1, invasion/migration assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor binding, downstream RAC1/ELMO1 signaling, and siRNA knockdown in a single lab\",\n      \"pmids\": [\"26756176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCL18 from ovarian cancer ascites promotes tumor cell migration via phosphorylation of proline-rich tyrosine kinase 2 (Pyk2); siRNA-mediated downregulation of Pyk2 attenuates ascites- and CCL18-induced cell migration.\",\n      \"method\": \"siRNA knockdown of Pyk2, ectopic Pyk2 expression, Boyden chamber migration assay, CCL18 blocking antibodies, Western blotting for phospho-Pyk2\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA and overexpression with blocking antibody in multiple OC cell lines\",\n      \"pmids\": [\"27613122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCL18 from TAMs activates NF-κB signaling via PITPNM3 in fibroblasts to enhance IL-6 and IL-8 production, converting normal breast-resident fibroblasts into a CD10+GPR77+ chemoresistance-inducing CAF phenotype.\",\n      \"method\": \"Co-culture systems, anti-CCL18 antibody blocking, Western blotting, siRNA/overexpression, in vivo CCL18 intratumoral injection xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic in vitro and in vivo validation with antibody rescue in a single lab\",\n      \"pmids\": [\"36418470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCL18 inhibits CCR1, CCR2, CCR4, and CCR5-mediated chemotaxis without binding to these receptors; instead, CCL18 selectively displaces heparin-bound chemokines from glycosaminoglycans (GAGs) on the endothelial surface, thereby functioning as a regulatory inhibitor of chemokine-mediated leukocyte recruitment.\",\n      \"method\": \"Schild plot analysis for competitive antagonism, binding assays to CCR-transfected cells, GAG displacement assays with heparin-bound chemokines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional antagonism with mechanistic GAG displacement assay, single lab\",\n      \"pmids\": [\"23951310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Adenoviral overexpression of CCL18 in mouse lungs induces massive perivascular and peribronchial T lymphocyte infiltration and T lymphocyte-dependent collagen accumulation; T cell depletion abrogates CCL18-induced collagen deposition; CCL18 prestimulation of T cells upregulates TGF-beta1, which drives collagen production in T lymphocyte/fibroblast cocultures.\",\n      \"method\": \"Adenoviral gene delivery in vivo, antilymphocyte serum depletion, immunohistochemistry, flow cytometry, ELISA, T lymphocyte/fibroblast coculture\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic delivery with depletion rescue experiment, multiple readouts\",\n      \"pmids\": [\"16868995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCL18 attenuates CXCL12/CXCR4-mediated responses (calcium mobilization, chemotaxis, pseudo-emperipolesis, proliferation) in pre-B ALL cells by binding to GPR30; antibodies against GPR30 abolished CCL18 binding and its functional effects.\",\n      \"method\": \"Calcium flux assays, chemotaxis assays, GPR30-blocking antibodies, CCL18 binding to GPR30-expressing cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — receptor binding and functional inhibition assays in a single lab; GPR30 identification as CCL18 receptor requires further corroboration\",\n      \"pmids\": [\"20568229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCL18 production by immature dendritic cells is selectively down-regulated during maturation (by LPS, TNF, CD40L, pathogens), whereas IL-10 and vitamin D3 strongly promote CCL18 secretion; CCL18 was found to be chemotactic for immature dendritic cells.\",\n      \"method\": \"Cytokine stimulation of monocyte-derived DCs, ELISA for CCL18, chemotaxis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional chemotaxis and secretion assays, single lab but comprehensive panel of stimuli\",\n      \"pmids\": [\"12646652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCL18 promotes breast cancer metastasis via Annexin A2 as a downstream molecule of Nir1 (PITPNM3); CCL18 upregulates AnxA2 which promotes invasion and metastasis through the PI3K/Akt/GSK3β/Snail signaling pathway and F-actin polymerization via integrin β1.\",\n      \"method\": \"Western blot, siRNA knockdown of AnxA2, PI3K inhibitor LY294002, F-actin measurement, Matrigel invasion assay, spontaneous metastasis in SCID mice\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo validation with siRNA and pharmacological inhibition\",\n      \"pmids\": [\"31894281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCL18 reduces miR98 and miR27b expression via the N-Ras/ERK/PI3K/NFκB/Lin28b signaling pathway, forming a positive feedback loop that sustains CCL18 signaling and promotes EMT and metastasis of breast cancer cells.\",\n      \"method\": \"miRNA expression profiling, pathway inhibitor studies, overexpression/knockdown of miR98 and miR27b, invasion/migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissection with miRNA and signaling inhibitors, single lab\",\n      \"pmids\": [\"26244871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCL18 promotes bladder cancer cell invasion, migration, and EMT by binding to CCR8; blocking CCR8 with a small molecule inhibitor or shRNA knockdown reverses CCL18-induced decrease in E-cadherin and increase in MMP-2 and VEGF-C.\",\n      \"method\": \"CCR8 shRNA knockdown, CCR8 small molecule inhibitor, Western blotting, invasion/migration assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor knockdown and pharmacological inhibition with mechanistic readouts, single lab\",\n      \"pmids\": [\"30592282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In glioma, CCR8 is identified as a functional receptor for CCL18; downstream signaling involves ACP5 (acid phosphatase 5), and CCL18 promotes glioma cell growth and invasion via the CCR8-ACP5 axis.\",\n      \"method\": \"Humanized brain slice model with iPSC-derived human microglia, CCR8 identification, in vivo GBM mouse model, functional invasion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel ex vivo and in vivo model with receptor and downstream signaling identification\",\n      \"pmids\": [\"35417708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Thrombin stimulates CCL18 release from mature dendritic cells (LPS-matured, PAR1/PAR3-expressing) via Rho-dependent signaling; CCL18 release requires ERK1/2 and Rho kinase activation.\",\n      \"method\": \"PAR-activating peptides, ERK1/2 and Rho kinase pharmacological inhibitors, ELISA for CCL18, actin polymerization assays, immunofluorescence\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of signaling pathway with multiple inhibitors in a single lab\",\n      \"pmids\": [\"18606675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACAP4 is acetylated by PCAF acetyltransferase at Lys311 in response to CCL18 stimulation; dynamic acetylation of ACAP4 is essential for CCL18-induced breast cancer cell migration and invasion by reducing ACAP4 lipid-binding activity to permit robust ARF6-ACAP4 plasma membrane cycling.\",\n      \"method\": \"Mass spectrometry, co-IP of ACAP4 with PCAF, acetylation-mimicking and non-acetylatable ACAP4 mutants, cell migration assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometric mapping of acetylation site, mutagenesis, and functional assays in a single lab\",\n      \"pmids\": [\"30395269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ezrin is acetylated by PCAF acetyltransferase in breast cancer cells in response to CCL18 stimulation; acetylation at the mapped site reduces ezrin lipid-binding activity, prevents Thr567 phosphorylation, and drives ezrin unfolding, enabling dynamic plasma membrane-cytosol cycling essential for CCL18-induced cell migration and invasion.\",\n      \"method\": \"Mass spectrometry, co-IP of ezrin with PCAF, atomic force microscopy, phosphorylation/acetylation mutants, cell migration assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry plus AFM structural analysis plus functional mutagenesis, single lab\",\n      \"pmids\": [\"31638145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCL18 activates the ARF6/Src/PI3K/Akt signaling pathway; CCL18 increases ARF6 expression and p-AMAP1 via suppression of miR-760 in high metastatic breast cancer cells; exosomal miR-760 secreted by CCL18-stimulated high-metastatic cells is taken up by low-metastatic cells and promotes ARF6-mediated Src/PI3K/Akt signaling and EMT.\",\n      \"method\": \"ARF6 knockdown, miR-760 mimic/inhibitor, exosome uptake assays, Western blotting, in vivo tumor growth/metastasis models\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ARF6 knockdown plus exosome mechanistic experiments with in vivo validation, single lab\",\n      \"pmids\": [\"35399607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The PARC/CCL18 gene was generated by fusion of two MIP-1alpha/LD78alpha-like genes on chromosome 17q11.2, explaining its high sequence similarity to MIP-1alpha but distinct chemotactic activity (toward lymphocytes rather than monocytes) and lack of shared receptor with MIP-1alpha.\",\n      \"method\": \"BAC clone genomic analysis, dot-plot sequence comparison, exon/intron structure analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genomic structural analysis establishing gene origin, single study\",\n      \"pmids\": [\"10049593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"M2-TAMs induce EMT of ovarian cancer cells by releasing CCL18; CCL18 induces M-CSF transcription in OvCa cells through ZEB1, and M-CSF drives M2 polarization of macrophages, establishing a CCL18-ZEB1-M-CSF positive feedback loop between OvCa cells and TAMs in spheroids.\",\n      \"method\": \"3D coculture, transwell coculture, RNA-sequencing, Western blot, qRT-PCR, ZEB1 knockdown, intraperitoneal mouse model\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — feedback loop dissected by ZEB1 knockdown in vitro and in vivo, single lab\",\n      \"pmids\": [\"34969774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lactate regulates CCL18 expression in macrophages via H3K18 lactylation; lactate-treated macrophages (acting through Gpr132) promote OV cell proliferation and migration, effects reversed by CCL18 silencing or anti-CCL18 antibody.\",\n      \"method\": \"ChIP-qPCR for H3K18 lactylation at CCL18 locus, luciferase reporter assay, Gpr132 siRNA knockdown, anti-CCL18 antibody, xenograft mouse model\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-qPCR epigenetic mechanism plus rescue experiments, single lab\",\n      \"pmids\": [\"39010846\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCL18, a primate-specific chemokine constitutively expressed in lung and plasma and abundantly produced by tumor-associated macrophages (M2-polarized), signals primarily through two identified receptors—PITPNM3 (Nir1) and CCR8—to activate downstream pathways including intracellular calcium signaling, Pyk2/Src kinase recruitment, NF-κB, PI3K/Akt, and ARF6/AMAP1, promoting integrin clustering, EMT, and cancer cell invasion/metastasis; it also stimulates collagen production in fibroblasts via PKCalpha/ERK2/Sp1 and basal Smad3 signaling, inhibits leukocyte recruitment by displacing chemokines from glycosaminoglycans, and has its own expression regulated epigenetically by H3K18 lactylation and transcriptionally by IL-4/IL-10/STAT6 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCL18 is a primate-specific CC-chemokine that functions as a pleiotropic mediator of immune regulation, tissue fibrosis, and cancer metastasis. It signals through two validated receptors—PITPNM3 (Nir1) and CCR8—to activate intracellular calcium flux, Pyk2/Src kinase cascades, NF-κB, PI3K/Akt, and ARF6 pathways, which collectively drive integrin clustering, cytoskeletal reorganization, epithelial-mesenchymal transition, and cancer cell invasion [PMID:21481794, PMID:23999500, PMID:24142406, PMID:26449829, PMID:35399607]. In fibroblasts, CCL18 stimulates collagen production through PKCα/ERK2/Sp1 signaling independently of autocrine TGF-β, and in vivo it promotes T lymphocyte-dependent pulmonary fibrosis [PMID:16601239, PMID:16021625, PMID:16868995]. CCL18 also attenuates leukocyte recruitment by displacing heparin-bound chemokines from glycosaminoglycans on endothelial surfaces, and its own expression in tumor-associated macrophages is regulated by IL-10, STAT6 signaling, and H3K18 lactylation at its promoter [PMID:23951310, PMID:12646652, PMID:39010846].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Determining CCL18's evolutionary origin resolved why it has lymphocyte-directed chemotactic activity distinct from its closest paralog MIP-1α despite high sequence identity.\",\n      \"evidence\": \"BAC clone genomic analysis showing CCL18 arose by fusion of two MIP-1α-like genes on 17q11.2\",\n      \"pmids\": [\"10049593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified at this stage\", \"Functional divergence from MIP-1α not tested beyond chemotaxis\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that CCL18 is constitutively produced by immature dendritic cells and suppressed upon maturation positioned it as a tolerogenic/anti-inflammatory chemokine, with IL-10 and vitamin D3 as key inducers.\",\n      \"evidence\": \"Cytokine stimulation panel of monocyte-derived DCs with ELISA and chemotaxis assays\",\n      \"pmids\": [\"12646652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating DC chemotaxis unknown\", \"In vivo relevance of DC-derived CCL18 not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Dissecting the pro-fibrotic signaling cascade showed that CCL18 stimulates collagen production in lung fibroblasts through calcium/PKCα/ERK2/Sp1 and basal Smad3, independent of autocrine TGF-β, and that in vivo CCL18 drives T cell-dependent pulmonary collagen deposition.\",\n      \"evidence\": \"Dominant-negative PKCα/ERK2/Sp1/Smad3 mutants, pharmacological inhibitors, adenoviral CCL18 delivery in mouse lungs with anti-lymphocyte serum depletion\",\n      \"pmids\": [\"16601239\", \"16021625\", \"16868995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fibroblast receptor for CCL18 not identified\", \"Relationship between direct fibroblast stimulation and T cell-mediated collagen deposition unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of PITPNM3 as a functional CCL18 receptor on breast cancer cells established the mechanistic basis for TAM-derived CCL18 driving integrin clustering, ECM adherence, and tumor invasiveness.\",\n      \"evidence\": \"Co-IP, calcium signaling, PITPNM3 siRNA knockdown, invasion assays, and xenograft mouse models\",\n      \"pmids\": [\"21481794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PITPNM3 structure-function relationship with CCL18 unresolved\", \"Whether PITPNM3 is the sole cancer-relevant receptor unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that CCR8 serves as a second high-affinity CCL18 receptor, and that CCL18 independently inhibits chemokine-mediated leukocyte recruitment by displacing GAG-bound chemokines, revealed dual receptor-dependent and receptor-independent immunomodulatory mechanisms.\",\n      \"evidence\": \"Competitive binding, calcium flux, chemotaxis on CCR8-transfected cells, Ccr8-KO Th2 cells; Schild plot analysis and GAG displacement assays\",\n      \"pmids\": [\"23999500\", \"23951310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of PITPNM3 vs CCR8 in different cell types not systematically compared\", \"GAG displacement mechanism not validated in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Elucidation of the Pyk2→Src kinase relay downstream of PITPNM3 established how CCL18 receptor engagement translates into integrin β1 clustering and cytoskeletal-dependent cell motility.\",\n      \"evidence\": \"Co-IP of Pyk2 with PITPNM3, immunofluorescence showing Pyk2 membrane translocation, Src activation by Western blot, invasion/adherence assays\",\n      \"pmids\": [\"24142406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural data on PITPNM3-Pyk2 interface\", \"Pyk2 phosphorylation site specificity not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that CCL18/PITPNM3 activates NF-κB (IKK/IκBα/p65) and N-Ras/ERK/PI3K/Lin28b pathways, and that CCL18 sustains its own signaling via miR-98/miR-27b suppression, broadened the downstream effector landscape to include EMT transcriptional programs.\",\n      \"evidence\": \"PITPNM3 siRNA in HCC cells; miRNA profiling, pathway inhibitors, overexpression/knockdown of miR-98 and miR-27b in breast cancer cells\",\n      \"pmids\": [\"26449829\", \"26244871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Positive feedback loop duration and in vivo relevance not established\", \"NF-κB and miRNA arms not tested for cross-talk\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of ELMO1/RAC1 as effectors of CCL18/Nir1 signaling in NSCLC and confirmation of Pyk2 in ovarian cancer migration generalized the Pyk2-integrin and RAC1-cytoskeleton axes across tumor types.\",\n      \"evidence\": \"ELMO1 siRNA, RAC1 activation assays in NSCLC; Pyk2 siRNA/overexpression with CCL18 blocking antibody in ovarian cancer\",\n      \"pmids\": [\"26756176\", \"27613122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ELMO1 and Pyk2 operate in the same or parallel branches not determined\", \"Upstream adapter linking PITPNM3 to RAC1/ELMO1 unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that CCL18 triggers PCAF-mediated acetylation of ACAP4 and ezrin revealed a post-translational regulatory layer governing ARF6 membrane cycling and ezrin conformational dynamics essential for cell migration.\",\n      \"evidence\": \"Mass spectrometry of acetylation sites, PCAF co-IP, acetylation-mimicking/non-acetylatable mutants, AFM structural analysis, migration assays\",\n      \"pmids\": [\"30395269\", \"31638145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CCL18 signal activates PCAF acetyltransferase not known\", \"ACAP4/ezrin acetylation not validated in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Convergent studies established CCL18 as a master organizer of the tumor microenvironment: it converts normal fibroblasts to chemoresistance-promoting CAFs via NF-κB/IL-6/IL-8, signals through CCR8-ACP5 in glioma, and propagates invasion via exosomal miR-760/ARF6.\",\n      \"evidence\": \"Co-culture with anti-CCL18 blocking, xenograft models; humanized brain slice and GBM mouse models; exosome uptake assays with ARF6 knockdown and in vivo metastasis\",\n      \"pmids\": [\"36418470\", \"35417708\", \"35399607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CAF conversion requires CCR8 or PITPNM3 on fibroblasts not tested\", \"Exosomal miR-760 mechanism awaits independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of H3K18 lactylation at the CCL18 promoter in macrophages linked tumor-derived lactate metabolism to epigenetic control of CCL18 transcription, closing a regulatory loop between tumor glycolysis and TAM-mediated immune evasion.\",\n      \"evidence\": \"ChIP-qPCR for H3K18 lactylation, luciferase reporter, Gpr132 siRNA, anti-CCL18 antibody rescue, xenograft model\",\n      \"pmids\": [\"39010846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide specificity of lactylation-driven CCL18 regulation not assessed\", \"Whether other epigenetic marks cooperate with H3K18la at the CCL18 locus unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CCL18 binding to PITPNM3 versus CCR8, the cell-type-specific partitioning of signaling between these receptors, and whether the GAG-displacement anti-inflammatory function operates in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of CCL18-receptor complexes\", \"No systematic genetic model distinguishing PITPNM3 vs CCR8 contributions in vivo\", \"GAG displacement function not validated in animal models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 9, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 9, 10, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 13, 14, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 10, 12, 17]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PITPNM3\",\n      \"CCR8\",\n      \"PYK2\",\n      \"ACAP4\",\n      \"ELMO1\",\n      \"PCAF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}