{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T05:36:02Z","timestamp":1767591362067,"version":"3.48.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"\n Background<\/jats:title>\n \n OPCML<\/jats:italic>\n (opioid-binding protein\/cell adhesion molecule-like), a glycosylphosphatidylinositol (GPI)-anchored IgLON adhesion molecule with brain-enriched expression, has tumor-suppressive roles in several epithelial cancers; however, its role in glioblastoma (GBM) biology is unclear.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We integrated two bulk microarray cohorts to derive a reproducible GBM signature and reanalyzed single-cell RNA sequencing (scRNA-seq) data to localize\n OPCML<\/jats:italic>\n at single-cell resolution. The tissue distribution and clinical associations were evaluated using the Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA), with survival modeling and a nomogram. The co-expression, STRING-based protein interaction, and Gene Ontology (GO)\/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses outlined the molecular context. Immune infiltration was profiled using single-sample gene set enrichment analysis (ssGSEA) and cross-checked on TIMER2. Functional validation used a single\n OPCML<\/jats:italic>\n small interfering RNA (siRNA) with a non-targeting siRNA control (siNC) in U87 and U251 cells with Transwell invasion, wound healing, colony formation, CCK-8 proliferation, and Western blotting for p-AKT and p-mTOR, with LY294002 rescue.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n OPCML<\/jats:italic>\n was consistently downregulated in GBM and across multiple cancers. Within GBM, a lower expression was associated with higher grade, older age, isocitrate dehydrogenase (\n IDH<\/jats:italic>\n ) wild type, and poorer overall survival. At the single-cell level, the\n OPCML<\/jats:italic>\n transcripts were largely confined to a neuron\u2013glia hybrid population and were scarce in classical malignant clusters. Genome-wide correlations in GBM showed positive links to extracellular matrix\/synaptic programs and negative links to cell cycle\/DNA replication pathways.\n In vitro<\/jats:italic>\n ,\n OPCML<\/jats:italic>\n knockdown increased the invasion, migration, clonogenic growth, and CCK-8 readouts and was associated with elevated p-AKT and p-mTOR. PI3K inhibition reversed the signaling changes. Pan-cancer,\n OPCML<\/jats:italic>\n tracked with denser immune signatures, whereas in GBM it was inversely correlated with multiple effector populations and with cancer-associated fibroblast (CAF) estimates across deconvolution methods.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n OPCML<\/jats:italic>\n marks a neuron-leaning, less aggressive state and is associated with the regulation of PI3K\u2013AKT\u2013mTOR signaling in GBM. Loss of\n OPCML<\/jats:italic>\n aligns with proliferative programs and a GBM-specific immune pattern. These data nominate\n OPCML<\/jats:italic>\n as a prognostic marker and a surface-level modulator that could be leveraged alongside RTK\/PI3K axis inhibitors in GBM.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fonc.2025.1710073","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T05:32:01Z","timestamp":1767591121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Downregulation of OPCML is associated with activation of AKT signaling and aggressive phenotypes in glioblastoma 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