{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nROR2 has emerged as a critical mediator in diverse cancers where it functions as a receptor or co‐receptor for non‐canonical Wnt ligands—most notably Wnt5a—to promote tumor aggressiveness. In tumors lacking primary cilia, ROR2 activates pathways that stimulate invadopodia formation, remodel the Golgi apparatus, and enhance cell invasiveness and migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In melanoma and other solid tumors, increased ROR2, often induced by Wnt5a, is linked with a switch toward a more invasive phenotype, reduced sensitivity to targeted therapies, and a significant role in metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similar findings in osteosarcoma and renal cell carcinoma implicate ROR2 in the induction of matrix metalloproteinases through Src-family kinases and establish its association with enhanced motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, ROR2 is upregulated in epithelial–mesenchymal transition driven by Snail, and its signaling can be transmitted via specialized structures such as cytonemes, thereby coordinating paracrine Wnt transport."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": " Additionally, ROR2-dependent signaling drives transcription of key invasion promoters such as MMP-13"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and alterations in non-canonical Wnt gene signatures further support its tumor-promoting role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In several carcinomas, epigenetic downregulation and subsequent rescue of ROR2 expression correlate with growth control, and its expression in multiple myeloma models underscores a role in niche adhesion and engraftment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Finally, recent evidence in endometrial cancer further supports the clinical relevance of ROR2 as a biomarker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of skeletal development and bone formation, ROR2 plays multifaceted roles by modulating both canonical and non‐canonical Wnt signaling in osteoblastic cells. ROR2 has been shown to physically interact with osteogenic ligands such as Wnt1 and Wnt3, thereby influencing the stabilization of β‐catenin and the transcriptional output of osteogenic genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Moreover, its dynamic regulation during osteoblast differentiation, supported by antibody-induced dimerization and subsequent autophosphorylation, positions ROR2 as a key promoter of bone formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Clinically, mutations in ROR2 that compromise its trafficking or signaling capacity cause severe skeletal dysplasias such as Robinow syndrome and brachydactyly, highlighting the necessity for proper receptor folding and membrane localization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Further genetic analyses reinforce that the degree of functional ROR2 present at the cell surface is critical to its developmental output"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and investigations in multiple myeloma models indicate that ROR2 contributes to the regulation of osteoblastic differentiation and bone remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in tumorigenesis and osteogenesis, ROR2 is also integral to non-canonical Wnt signaling mechanisms that govern cell polarity and tissue patterning. While canonical Wnt signaling predominantly relies on β‐catenin stabilization, ROR2 mediates β‐catenin–independent pathways that are essential during organogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " Reviews and focused studies have underscored an apparent dual role for ROR2 in tumorigenesis, functioning as either a tumor promoter or suppressor depending on cellular context."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " In addition, ligand-induced dimerization activates its kinase domain—albeit atypical, with evidence suggesting ROR2 behaves as a pseudokinase in human cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " Intriguingly, the identification of cell-surface marker combinations including ROR2 in differentiating cardiac mesoderm implicates the receptor in early cardiovascular lineage specification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging studies further extend ROR2’s functional repertoire to other biological systems. 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