{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nA number of genome‐wide association studies have implicated the TSPAN8 region in metabolic regulation, most notably in type 2 diabetes. The TSPAN8‐LGR5 locus has been reproducibly associated with T2D risk, and several analyses have demonstrated that variants in TSPAN8 influence beta‐cell function and associated glycemic traits, underscoring a role for TSPAN8 in the genetic architecture of diabetes. These findings suggest that even modest alterations in TSPAN8 expression or function might contribute to impaired insulin secretion and beta‐cell dysfunction seen in T2D."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its metabolic implications, TSPAN8 has been linked to neuropsychiatric disorders. Genome‐wide scans in bipolar disorder identified associations with TSPAN8, and further analysis of single nucleotide polymorphisms in the TSPAN8 gene suggests that differential promoter activity and even amino acid changes may underlie distinct contributions of TSPAN8 to bipolar disorder versus schizophrenia, indicating that its regulatory or structural modifications might differentially impact neuronal function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA multitude of studies have revealed that TSPAN8 plays diverse and critical roles in cancer progression. In several tumor types, TSPAN8 overexpression has been linked to enhanced invasiveness, metastatic potential, and therapy resistance. In malignant glioma, increased TSPAN8 expression fosters cell proliferation, migration, and resistance to chemotherapeutic agents through its interaction with activated focal adhesion kinase"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while in gastric cancer, TSPAN8 serves as a potential biomarker for tumor identification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In metastatic colorectal cancer, targeting the large extracellular loop of TSPAN8 with a high‐affinity human antibody significantly reduces tumor cell invasiveness"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and in hepatocellular carcinoma, up‐regulation of TSPAN8—either through transcriptional activation by oncogenes such as AEG‐1 or via increased ADAM12m expression—has been shown to promote invasion and metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In melanoma, TSPAN8 is engaged in a positive feedback loop with β‐catenin that sustains high TSPAN8 levels, leading to diminished cell–matrix adhesion via modulation of the β1 integrin–ILK axis and promoting an invasive phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Furthermore, in breast cancer, TSPAN8 expression in both primary lesions and metastases has been implicated in the regulation of epithelial–mesenchymal transition, with effects on cell–cell adhesion and extracellular vesicle release that further contribute to tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": " A comprehensive review has highlighted the physiological roles of TSPAN8—including its participation in leukocyte trafficking, angiogenesis, and wound repair—and its emerging importance as a therapeutic target in various cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In non–small cell lung cancer, TSPAN8 is enriched on extracellular vesicles, where its elevated surface levels correlate with future metastasis and may serve as a minimally invasive biomarker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " In pancreatic ductal adenocarcinoma, TSPAN8 has emerged both as a target for CAR T cell therapy and as a key effector of the EGF–SOX9–TSPAN8 signaling cascade that drives invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Moreover, studies of small extracellular vesicles show that TSPAN8 promotes confined diffusion at the cell surface and enhances epithelial–mesenchymal transition as well as cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Notably, an unconventional pathway of nuclear translocation has been described for TSPAN8, wherein EGFR–AKT signaling mediates its phosphorylation and subsequent interaction with STAT3 to modulate the transcription of oncogenic genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eleftheria Zeggini, Laura J Scott, Richa Saxena, et al. 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