{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nROR1 is a receptor tyrosine kinase–like orphan receptor normally expressed during embryogenesis and largely absent in adult tissues, yet it becomes re‐expressed in a broad range of hematologic and solid malignancies. Numerous studies have shown that this oncofetal antigen is expressed in chronic lymphocytic leukemia, precursor B‐cell acute lymphoblastic leukemia, breast, ovarian and other cancers, where its presence correlates with aggressive disease and enhanced tumor cell survival, proliferation, and self‐renewal. Moreover, distinct isoforms and post‐translational modifications of ROR1 have been described in malignant cells, indicating that aberrant regulation of this receptor contributes to oncogenesis and tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nROR1 exerts its oncogenic functions through a variety of interconnected signaling mechanisms. It can bind to ligands such as Wnt5a to trigger both canonical and noncanonical signaling cascades that modulate cell migration, invasion, and epithelial–mesenchymal transition. In several studies, ROR1 engagement has been linked to the regulation of key effectors – including HER3, AKT, CREB and small GTPases like Rac1 and RhoA – either via direct phosphorylation, through scaffolding interactions with partners such as casein kinase 1ε and HS1, or even via transphosphorylation by enzymes like Met. In addition, genetic variations and regulatory microRNAs further fine‐tune ROR1 activity, underscoring its multifaceted role in tumor cell signaling and its potential involvement in disorders beyond cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGiven its tumor‐restricted surface expression and its central role in key signaling pathways, ROR1 has emerged as an attractive diagnostic marker and therapeutic target. Its cell surface expression has been leveraged for the design of targeted immunotherapies—including monoclonal antibodies and chimeric antigen receptor (CAR) T cells—that have shown promise in preclinical models across diverse cancers, including sarcomas and colorectal as well as pediatric malignancies. In addition, reports of ROR1‐involved gene fusions and associations with adverse clinical outcomes further underscore its prognostic potential. However, some studies also report low‐level ROR1 expression in select normal tissues, a factor that will require careful safety monitoring in the clinical translation of ROR1‐targeted therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael Hudecek, Maria-Teresa Lupo-Stanghellini, Paula L Kosasih, et al. 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